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Abstract:

Provided herein are substituted furanyl compounds of formula (I),
pharmaceutical compositions comprising the compounds, methods of their
preparation, and methods of their use. The compounds provided herein are
useful for the treatment, prevention, and/or amelioration of various
disorders, including cancer and proliferative disorders. In one
embodiment, the compounds provided herein modulate eIF4E activity. In one
embodiment, the compounds provided herein modulate the Hedgehog pathway
activity. In one embodiment, the compounds provided herein are used in
combination with surgery, radiation therapy, immuno therapy and/or one or
more additional anticancer drugs for the treatment, prevention, and/or
amelioration of cancer and proliferative disorders.

Claims:

1. A compound of formula (I): ##STR00034## or an enantiomer, a mixture
of enantiomers, or a mixture of two or more diastereomers thereof; or a
pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof;
wherein: (A) L is S(O)2; R1 is phenyl or (6 membered)
heteroaryl, each of which is optionally substituted with one or more
halogen, cyano, R2, OR5, OC(O)R5, C(O)R5,
C(O)OR5, C(O)NR5R6, NR5C(O)R6, NR5R6,
OS(O)R5, SR5, S(O)R5, S(O)2R5,
S(O)2NR5R6, or NR5S(O)2R6; each occurrence
of R2 is (i) (C1-C8)alkyl, (C2-C8)alkenyl, or
(C2-C8) alkynyl, each of which is optionally substituted with
one or more halogen, cyano, OR5, OC(O)R5, C(O)R5,
C(O)OR5, C(O)NR5R6, NR5C(O)R6, NR5R6,
OS(O)R5, SR5, S(O)R5, S(O)2R5,
S(O)2NR5R6, NR5S(O)2R6,
(C1-C8)heteroalkyl, (C3-C8)cycloalkyl, (6 to 10
membered) aryl, (5 to 10 membered)heteroaryl, or (3 to 10
membered)heterocyclyl; wherein the heteroalkyl, cycloalkyl, aryl,
heteroaryl and heterocyclyl are each optionally substituted with one or
more (C1-C6)alkyl, (C2-C6)alkenyl,
(C2-C6)alkynyl, halogen, cyano, OR5, OC(O)R5,
C(O)R5, C(O)OR5, C(O)NR5R6, NR5C(O)R6,
NR5R6, OS(O)R5, SR5, S(O)R5, S(O)2R5,
S(O)2NR5R6, or NR5S(O)2R6; or (ii)
(C3-C8)cycloalkyl optionally substituted with one or more
halogen, cyano, OR5, OC(O)R5, C(O)R5, C(O)OR5,
C(O)NR5R6, NR5C(O)R6, NR5R6, OS(O)R5,
SR5, S(O)R5, S(O)2R5, S(O)2NR5R6,
NR5S(O)2R6, (C1-C8)alkyl, (C2-C8)
alkenyl, (C2-C8) alkynyl, (C1-C8) heteroalkyl,
(C3-C8)cycloalkyl, (6 to 10 membered) aryl, (5 to 10
membered)heteroaryl, or (3 to 10 membered)heterocyclyl; wherein the
alkyl, alkenyl and alkynyl are each optionally substituted with one or
more halogen, cyano, OR5, OC(O)R5, C(O)R5, C(O)OR5,
C(O)NR5R6, NR5C(O)R6, NR5R6, OS(O)R5,
SRs, S(O)R5, S(O)2R5, S(O)2NR5R6, or
NR5S(O)2R6; and the heteroalkyl, cycloalkyl, aryl,
heteroaryl and heterocyclyl are each optionally substituted with one or
more (C1-C6)alkyl, (C2-C6) alkenyl,
(C2-C6)alkynyl, halogen, cyano, OR5, OC(O)R5,
C(O)R5, C(O)OR5, C(O)NR5R6, NR5C(O)R6,
NR5R6, OS(O)R5, SRS, S(O)R5, S(O)2R5,
S(O)2NR5R6, or NR5S(O)2R6; R3 is
hydrogen or R2; R4 is phenyl or (5 to 6 membered) heteroaryl,
each of which is optionally substituted with one or more halogen, cyano,
R2, ORs, OC(O)R5, C(O)R5, C(O)OR5,
C(O)NR5R6, NR5C(O)R6, NR5R6, OS(O)R5,
SRs, S(O)R5, S(O)2R5, S(O)2NR5R6,
NR5S(O)2R6, optionally substituted (6 to 10 membered)aryl,
optionally substituted (5 to 10 membered)heteroaryl, or optionally
substituted (3 to 10 membered)heterocyclyl; and R5 and R6 are
each independently hydrogen, (C1-C8)alkyl, (C2-C8)
alkenyl, (C2-C8)alkynyl, (C1-C8)heteroalkyl,
(C3-C8)cycloalkyl, (C7-C12)aralkyl, phenyl, (5 to 6
membered)heteroaryl, or (3 to 7 membered)heterocyclyl; or R5 and
R6 together form a 3 to 10 membered ring; or (B) L is C(O); R1
is phenyl or (5 to 6 membered)heteroaryl, each of which is optionally
substituted with one or more halogen, cyano, R2, ORs,
OC(O)R5, C(O)R5, C(O)OR5, C(O)NR5R6,
NR5C(O)R6, NR5R6, OS(O)R5, SR5,
S(O)R5, S(O)2R5, S(O)2NR5R6, or
NR5S(O)2R6; each occurrence of R2 is (i)
(C1-C8)alkyl, (C2-C8)alkenyl, or (C2-C8)
alkynyl, each of which is optionally substituted with one or more
halogen, cyano, ORs, OC(O)R5, C(O)R5, C(O)OR5,
C(O)NR5R6, NR5C(O)R6, NR5R6, OS(O)R5,
SR5, S(O)R5, S(O)2R5, S(O)2NR5R6,
NR5S(O)2R6, (C1-C8)heteroalkyl,
(C3-C8)cycloalkyl, (6 to 10 membered) aryl, (5 to 10
membered)heteroaryl, or (3 to 10 membered)heterocyclyl; wherein the
heteroalkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are each
optionally substituted with one or more (C1-C6)alkyl,
(C2-C6)alkenyl, (C2-C6)alkynyl, halogen, cyano,
OR5, OC(O)R5, C(O)R5, C(O)OR5, C(O)NR5R6,
NR5C(O)R6, NR5R6, OS(O)R5, SR5,
S(O)R5, S(O)2R5, S(O)2NR5R6, or
NR5S(O)2R6; or (ii) (C3-C8)cycloalkyl optionally
substituted with one or more halogen, cyano, OR5, OC(O)R5,
C(O)R5, C(O)OR5, C(O)NR5R6, NR5C(O)R6,
NR5R6, OS(O)R5, SR5, S(O)R5, S(O)2R5,
S(O)2NR5R6, NR5S(O)2R6,
(C1-C8)alkyl, (C2-C8) alkenyl, (C2-C8)
alkynyl, (C1-C8) heteroalkyl, (C3-C8)cycloalkyl, (6
to 10 membered) aryl, (5 to 10 membered)heteroaryl, or (3 to 10
membered)heterocyclyl; wherein the alkyl, alkenyl and alkynyl are each
optionally substituted with one or more halogen, cyano, OR5,
OC(O)R5, C(O)R5, C(O)OR5, C(O)NR5R6,
NR5C(O)R6, NR5R6, OS(O)R5, SR5,
S(O)R5, S(O)2R5, S(O)2NR5R6, or
NR5S(O)2R6; and the heteroalkyl, cycloalkyl, aryl,
heteroaryl and heterocyclyl are each optionally substituted with one or
more (C1-C6)alkyl, (C2-C6) alkenyl,
(C2-C6)alkynyl, halogen, cyano, OR5, OC(O)R5,
C(O)R5, C(O)OR5, C(O)NR5R6, NR5C(O)R6,
NR5R6, OS(O)R5, SR5, S(O)R5, S(O)2R5,
S(O)2NR5R6, or NR5S(O)2R6; R3 is
hydrogen or R2; R4 is ##STR00035## wherein (i) each X is
independently N or CH; and R7 and R8 are each independently
halogen or CF3; (ii) R9 is chloro or CF3; R10 is
fluoro, chloro, or CF3; and R11 is hydrogen, fluoro, chloro,
CF3, or (C1-C4)alkyl; R5 and R6 are each
independently hydrogen, (C1-C8)alkyl, (C2-C8)
alkenyl, (C2-C8)alkynyl, (C1-C8)heteroalkyl,
(C3-C8)cycloalkyl, (C7-C12)aralkyl, phenyl, (5 to 6
membered)heteroaryl, or (3 to 7 membered)heterocyclyl; or R5 and
R6 together form a 3 to 10 membered ring; and (i) when R7 and
R8 are both CF3 and X is CH, R1 is not 3,4-dichlorophenyl
or 3,5-dichlorophenyl; and (ii) when R9 and R10 are both
CF3 and R11 is hydrogen, R1 is not 3,4-dichlorophenyl or
3,5-dichlorophenyl.

2. The compound of claim 1, wherein L is S(O).sub.2.

3. The compound of claim 1, wherein L is C(O).

4. The compound of claim 3, wherein R4 is ##STR00036##

5. The compound of claim 3, wherein R4 is ##STR00037##

6. The compound of claim 5, having formula (V): ##STR00038## or an
enantiomer, a mixture of enantiomers, or a mixture of two or more
diastereomers thereof; or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof; wherein: R2 is CH3 or CF3;
R3 is hydrogen, (C1-C4)alkyl, or benzyl; R9 is chloro
or CF3; R10 is fluoro, chloro, or CF3; R11 is
hydrogen, fluoro, chloro, CF3, or (C1-C4)alkyl; R12
is fluoro, chloro, bromo, methyl, hydroxyl, or methoxyl, n is 0, 1, or 2;
and when R9 and R10 are both CF3, R11 is hydrogen,
and n is 2; then R12 is not chloro.

8. A pharmaceutical composition comprising a compound of claim 1, or an
enantiomer, a mixture of enantiomers, or a mixture of two or more
diastereomers thereof, or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof, and at least one pharmaceutically acceptable
excipient or carrier.

9. The pharmaceutical composition of claim 8, further comprising one or
more additional active agents.

10. A method of treating, preventing, or ameliorating one or more
symptoms of a disorder mediated by cap-dependent protein translation,
comprising administering a compound of claim 1, or an enantiomer, a
mixture of enantiomers, or a mixture of two or more diastereomers
thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or
prodrug thereof.

11. A method of treating, preventing, or ameliorating one or more
symptoms of a disorder mediated by eIF4E, comprising administering a
compound of claim 1, or an enantiomer, a mixture of enantiomers, or a
mixture of two or more diastereomers thereof, or a pharmaceutically
acceptable salt, solvate, hydrate, or prodrug thereof.

12. A method of treating, preventing, or ameliorating one or more
symptoms of a disorder mediated by the Hedgehog pathway, comprising
administering a compound of claim 1, or an enantiomer, a mixture of
enantiomers, or a mixture of two or more diastereomers thereof, or a
pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

15. The method of claim 14, wherein the cancer is resistant to
conventional therapy.

16. The method of claim 14, wherein the cancer is vincristine-resistant.

17. The method of claim 14, wherein the cancer is taxol-resistant.

18. The method of claim 14, wherein the cancer is cytarabine-resistant.

19. The method of claim 14, wherein the cancer is doxorubicin-resistant.

Description:

[0001] This application claims priority to U.S. Provisional Patent
Application No. 61/352,308, filed Jun. 7, 2010, which is incorporated by
reference herein in its entirety.

FIELD

[0002] Provided herein are substituted furanyl compounds, pharmaceutical
compositions comprising the compounds, methods of their preparation, and
methods of their use. The compounds provided herein are useful for the
treatment, prevention, and/or amelioration of various disorders,
including cancer, proliferative disorders, and angiogenesis mediated
diseases.

BACKGROUND

[0003] Cancer is a major worldwide public health problem; in the United
States alone, approximately 560,000 people died of cancer in 2006. See,
e.g., U.S. Mortality Data 2006, National Center for Health Statistics,
Centers for Disease Control and Prevention (2010). Many types of cancer
have been described in the medical literature. Examples include cancer of
blood, bone, skin, lung, colon, breast, prostate, ovary, brain, kidney,
bladder, pancreas, and liver, among others. The incidence of cancer
continues to climb as the general population ages and as new forms of
cancer develop. A continuing need exists for effective therapies to treat
subjects with cancer.

[0004] Breast cancer is one of the most common types of cancer, especially
among women. In the United States, there are about 194,000 new cases of
breast cancer and about 40,610 deaths from breast cancer in 2009. See,
e.g., Breast Cancer Statistics, National Cancer Institute (2010),
available at www.cancer.gov. Among different types of breast cancer,
triple negative breast cancer (estrogen receptor(ER)/progesterone
receptor/HER-2 negative) is more aggressive than other breast cancer
subtypes. No targeted therapy exists for triple negative breast cancer.
Triple negative breast cancer has a higher rate of recurrence resulting
in death, although the tumors initially appear to respond to
chemotherapy. Clearly there is a need to develop effective targeted
therapy for triple negative breast cancer.

[0005] The Hedgehog (Hh) signaling pathway directs tissue development in
embryo, and contributes to tissue homeostasis in adults. Deficient Hh
signaling results in defective embryogenesis. Conversely, excessive Hh
signaling is associated with an inherited cancer predisposition syndrome
(Gorlin Syndrome), and a number of human cancers, including basal cell
carcinoma and medulloblastoma. Multiple components of the Hh pathway can
be altered in tumors. Studies in tumor cell lines have identified targets
that can be exploited for the discovery of human Hh antagonists. Sonic
hedgehog, a mammalian version of hedgehog protein, has been shown to
stimulate the proliferation of several types of adult stem cells.

[0006] The Hh signal is relayed by Patched (Ptc), a 12-transmembrane
protein and Smoothened (Smo), a 7-transmembrane protein. Upon binding of
the Hh ligand to Ptc, the normal inhibitory effect of Ptc on Smo is
relieved, allowing Smo to transduce the Hh signal across the plasma
membrane. The signaling cascade initiated by Smo results in activation of
Gli transcription factors that translocate into the nucleus where they
control transcription of target genes. Smo is the therapeutic target of
many drugs designed to treat hedgehog pathway-related diseases including
many types of cancers and limb formation abnormalities such as
Brachydactyl).

[0007] A tight control of the Hh pathway activity is required for proper
cellular differentiation and organ formation. Uncontrolled activation of
the Hh signaling pathway is associated with malignancies, in particular,
those of the brain, skin and muscle, as well as angiogenesis. The Hh
pathway has been shown to regulate cell proliferation in adults by the
activation of genes involved in cell cycle progression, such as cyclin D,
which is involved in the G1-S transition. Sonic hedgehog blocks cell
cycle arrest mediated by p21, an inhibitor of cyclin dependent kinases.
Hh signaling also induces components in the EGFR pathway (EGF, Her2)
involved in proliferation and components in the PDGF (PDGFα) as
well as VEGF pathways involved in angiogenesis. Loss-of-function
mutations in the Ptc gene have been identified in patients with basal
cell nevus syndrome, a hereditary disease characterized by multiple basal
cell carcinomas. Dysfunctional Ptc gene mutations have also been
associated with a large percentage of sporadic basal cell carcinoma
tumors. Loss of Ptc function is thought to cause the uncontrolled Smo
signaling in basal cell carcinoma. Activating Smo mutations have been
identified in sporadic basal cell carcinoma tumors.

[0008] Changes in protein synthesis are directly linked to multiple human
cancers. Translation initiation is deregulated in many cancers,
including, e.g., lymphoma, breast cancer, head and neck cancer,
colorectal cancer, lung cancer, bladder cancer, cervical cancer, and
prostate cancer. Many proteins supporting the high rate of cancer cell
growth, proliferation, and survival are translated from mRNAs having
secondary structures, which have a greater dependence on rate-limiting
translation factors such as eukaryotic initiation factor 4E (eIF4E).
eIF4E overexpression in tumors can be a predictor for relapse in breast
cancer regardless of nodal status and for drug resistance to adjuvant
chemotherapy. A high percentage (>60%) of triple negative breast
tumors express high levels of eIF4E. The patient group with high levels
of eIF4E has a 1.6-fold higher rate of recurrence and a 2.1-fold increase
in relative risk for cancer death. High levels of eIF4E drive the
cap-dependent translation of proteins responsible for cancer initiation
and progression resulting in aggressive phenotypes and enabling the
tumors to better survive radiation treatment and chemotherapy. Therefore,
it is desirable to regulate protein translation in cancer, in particular,
inhibit the rate-limiting steps in protein translation in order to
control cell growth and proliferation.

[0009] eIF4E, the rate-limiting factor for eukaryotic cap-dependent
protein translation, is ubiquitously expressed in multiple breast cancer
cell lines. The activity and availability of eIF4E are controlled, e.g.,
by binding proteins such as 4E-BP1. The activity of these binding
proteins is in turn regulated by phosphorylation, particularly by mTOR.
eIF4E over-expression along with the concomitant enhanced cap-dependent
translation drives cellular transformation and tumorigenesis. eIF4E is a
convergence point for many oncogenic pathways and a key factor for
malignancy in human cancer tissues and in experimental cancer models.
Enhanced translation initiation is found in malignant breast phenotypes.
eIF4E over-expression leads to breast carcinoma angiogenesis and
progression. eIF4E elevation of 7-fold or more is a strong independent
prognostic indicator for breast cancer relapse and death in retrospective
and prospective studies. Antisense oligonucleotide therapy
down-regulating eIF4E resulted in a reduction of in vivo tumor growth in
PC-3 prostate and MDA-MB-231 breast cancer models in mice. No toxicity
was observed when 80% knockdown was observed in essential organs,
suggesting tumors are more sensitive to cap-dependent translation
inhibition than normal tissue.

[0010] Cap-dependent translation initiation factor eIF4E and its binding
protein 4E-BP1 are major downstream effectors of the PI3K/Akt/mTOR
pathway. mTOR and other members of the PI3K/Akt/mTOR family control the
establishment and maintenance of cancer phenotypes. The PI3K/Akt/mTOR
pathway has been clinically validated as target for cancer therapies.
Overactivation of PI3K and Akt is found in a wide range of tumor types.
PI3K catalyzes the production of
phosphatidylinositol-3,4,5-trisphosphate. This lipid activates Akt
protein kinase, which in turn triggers a cascade of responses ranging
from cell growth and proliferation to survival and motility. PTEN, a dual
specificity phosphatase, is an inhibitor of the PI3K pathway. Second to
p53, PTEN is most frequently mutated or deleted in human tumors. Several
PI3K inhibitors have been developed in clinical trials. However, due to
the integral roles of PI3K and Akt in insulin signaling, it is likely
that inhibition of PI3K and Akt activities can lead to abrogated insulin
function. Experimental evidence from preclinical models suggests that the
blockade of PI3K and Akt results in the loss of insulin signaling in the
peripheral tissues and in pancreatic beta cells, potentially leading to
hyperglycemia and diabetes. This on-target side effect may limit the
therapeutic utility of PI3K and/or Akt inhibitors.

[0011] mTOR controls cap-dependent translation through phosphorylation and
inactivation of 4E-BP binding protein, thereby activating eIF4E.
Activation of eIF4E is required for the translation initiation of mRNAs
that have long structured '5-untranslated regions. Increasing evidence
suggests that mTOR, as a central regulator of cell growth and
proliferation, controls protein biosynthesis. The mTOR pathway controls
translation of mRNAs encoding proteins such as cyclin D1, c-Myc, and
ornithine decarboxylase that are essential for G1 cell-cycle progression
and S-phase initiation. Inhibition of mTOR results in G1 cell cycle
arrest. Rapamycin, an mTOR inhibitor, has significant antitumor activity
against many tumor cell lines in the NCI screening as well as in humans.
However, formulation, solubility and stability issues have hindered the
development of rapamycin. Analogs of rapamycin have been developed to
address these issues and have shown promising results in Phase II/III
clinical trials. However, preclinical studies and sequential biopsies in
patients from a Phase I trial of mTOR inhibitor showed that mTOR
inhibition activates Akt via an induced feedback loop. Furthermore,
inhibition of mTOR with rapamycin caused exacerbation of diabetes because
mTOR serves an important role in insulin signaling.

[0012] Therefore, there remains a need for alternative cancer therapeutic
agents that are effective and safe, e.g., agents having maximum
inhibition of tumor growth, minimal toxicity to normal cells, and minimal
on-target side effects in the treated subjects.

SUMMARY

[0013] Provided herein are compounds of formula (I), or an enantiomer, a
mixture of enantiomers or a mixture of diastereomers thereof, or a
pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof:

##STR00001##

wherein R1, R2, R3, R4, and L are defined herein
elsewhere. The compounds are useful for the treatment, prevention, and/or
amelioration of various disorders, such as cancer and proliferative
disorders.

[0014] Also provided herein are pharmaceutical compositions and dosage
forms comprising a compound provided herein, e.g., a compound of formula
(I), or an enantiomer, a mixture of enantiomers or a mixture of
diastereomers thereof, or a pharmaceutically acceptable salt, solvate,
hydrate or prodrug thereof. In one embodiment, the pharmaceutical
compositions and dosage forms further comprise one or more
pharmaceutically acceptable carriers or excipients. In one embodiment,
the compositions and dosage forms provided herein further comprise one or
more additional active agents, such as, e.g., a cancer therapeutic agent.

[0016] In one embodiment, provided herein is a method of inhibiting or
reducing the activity of the Hedgehog pathway. In one embodiment, the
method comprises contacting one or more receptors in the Hedgehog pathway
with a compound provided herein, e.g., a compound of formula (I), or an
enantiomer, a mixture of enantiomers or a mixture of diastereomers
thereof, or a pharmaceutically acceptable salt, solvate, hydrate or
prodrug thereof.

[0017] In one embodiment, provided herein is a method of inhibiting or
reducing the activity of eIF4E. In one embodiment, the method comprises
disrupting the eIF4F complex with a compound provided herein, e.g., a
compound of formula (I), or an enantiomer, a mixture of enantiomers or a
mixture of diastereomers thereof, or a pharmaceutically acceptable salt,
solvate, hydrate or prodrug thereof. In one embodiment, the method
comprises downregulating cap-dependent protein translation initiation
with a compound provided herein, e.g., a compound of formula (I), or an
enantiomer, a mixture of enantiomers or a mixture of diastereomers
thereof, or a pharmaceutically acceptable salt, solvate, hydrate or
prodrug thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

[0018] FIG. 1 illustrates the effect of Compounds 1 and 2 on inhibiting in
vivo tumor growth in the MDA-MB-468 xenograft model for breast cancer in
SCID mice (e.g., tumor volume and percent weight change in treated and
control animals).

DETAILED DESCRIPTION

[0019] Unless defined otherwise, all technical and scientific terms used
herein have the same meaning as those commonly understood by one of
ordinary skill in the art. All publications and patents referred to
herein are incorporated by reference herein in their entireties.

A. DEFINITIONS

[0020] As used in the specification and the accompanying claims, the
indefinite articles "a" and "an" and the definite article "the" include
plural as well as singular referents, unless the context clearly dictates
otherwise.

[0021] As used herein, and unless otherwise indicated, the term "about" or
"approximately" means an acceptable error for a particular value as
determined by one of ordinary skill in the art, which depends in part on
how the value is measured or determined. In certain embodiments, the term
"about" or "approximately" means within 1, 2, 3, or 4 standard
deviations. In certain embodiments, the term "about" or "approximately"
means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%,
0.5%, or 0.05% of a given value or range.

[0022] As used herein, and unless otherwise indicated, the term "alkyl"
refers to a linear or branched saturated monovalent hydrocarbon radical,
wherein the alkyl may optionally be substituted with one or more
substituents. The term "alkyl" also encompasses both linear and branched
alkyl, unless otherwise specified. In certain embodiments, the alkyl is a
linear saturated monovalent hydrocarbon radical that has 1 to 20
(C1-20), 1 to 15 (C1-15), 1 to 12 (C1-12), 1 to 10
(C1-10), or 1 to 6 (C1-6) carbon atoms, or branched saturated
monovalent hydrocarbon radical of 3 to 20 (C3-20), 3 to 15
(C3-15), 3 to 12 (C3-12), 3 to 10 (C3-10), or 3 to 6
(C3-6) carbon atoms. As used herein, linear C1-6 and branched
C3-6 alkyl groups are also referred as "lower alkyl." Examples of
alkyl groups include, but are not limited to, methyl, ethyl, propyl
(including all isomeric forms), n-propyl, isopropyl, butyl (including all
isomeric forms), n-butyl, isobutyl, t-butyl, pentyl (including all
isomeric forms), and hexyl (including all isomeric forms). For example,
C1-6 alkyl refers to a linear saturated monovalent hydrocarbon
radical of 1 to 6 carbon atoms or a branched saturated monovalent
hydrocarbon radical of 3 to 6 carbon atoms.

[0023] As used herein, and unless otherwise specified, the term "alkenyl"
refers to a linear or branched monovalent hydrocarbon radical, which
contains one or more, in one embodiment, one to five, carbon-carbon
double bonds. The alkenyl may be optionally substituted one or more
substituents. The term "alkenyl" also encompasses radicals having "cis"
and "trans" configurations, or alternatively, "E" and "Z" configurations,
as appreciated by those of ordinary skill in the art. As used herein, the
term "alkenyl" encompasses both linear and branched alkenyl, unless
otherwise specified. For example, C2-6 alkenyl refers to a linear
unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or a
branched unsaturated monovalent hydrocarbon radical of 3 to 6 carbon
atoms. In certain embodiments, the alkenyl is a linear monovalent
hydrocarbon radical of 2 to 20 (C2-20), 2 to 15 (C2-15), 2 to
12 (C2-12), 2 to 10 (C2-10), or 2 to 6 (C2-6) carbon
atoms, or a branched monovalent hydrocarbon radical of 3 to 20
(C3-20), 3 to 15 (C3-15), 3 to 12 (C3-12).sub., 3 to 10
(C3-10), or 3 to 6 (C3-6) carbon atoms. Examples of alkenyl
groups include, but are not limited to, ethenyl, propen-1-yl,
propen-2-yl, allyl, butenyl, and 4-methylbutenyl.

[0024] As used herein, and unless otherwise specified, the term "alkynyl"
refers to a linear or branched monovalent hydrocarbon radical, which
contains one or more, in one embodiment, one to five, carbon-carbon
triple bonds. The alkynyl may be optionally substituted one or more
substituents. The term "alkynyl" also encompasses both linear and
branched alkynyl, unless otherwise specified. In certain embodiments, the
alkynyl is a linear monovalent hydrocarbon radical of 2 to 20
(C2-20), 2 to 15 (C2-15), 2 to 12 (C2-12), 2 to 10
(C2-10), or 2 to 6 (C2-6) carbon atoms, or a branched
monovalent hydrocarbon radical of 3 to 20 (C3-20), 3 to 15
(C3-15).sub., 3 to 12 (C3-12).sub., 3 to 10 (C3-10), or 3
to 6 (C3-6) carbon atoms. Examples of alkynyl groups include, but
are not limited to, ethynyl (--C≡CH) and propargyl
(--CH2C≡CH). For example, C2-6 alkynyl refers to a linear
unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or a
branched unsaturated monovalent hydrocarbon radical of 3 to 6 carbon
atoms.

[0025] As used herein, and unless otherwise specified, the term
"cycloalkyl" refers to a cyclic saturated bridged and/or non-bridged
monovalent hydrocarbon radical, which may be optionally substituted one
or more substituents as described herein. In certain embodiments, the
cycloalkyl has from 3 to 20 (C3-20), from 3 to 15 (C3-15), from
3 to 12 (C3-12), from 3 to 10 (C3-10), or from 3 to 7
(C3-7) carbon atoms. Examples of cycloalkyl groups include, but are
not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, decalinyl, and adamantyl.

[0026] As used herein, and unless otherwise specified, the term
"heteroalkyl" refers to a stable straight or branched chain, or cyclic
hydrocarbon radical, or combinations thereof, consisting of the stated
number of carbon atoms and from one to three heteroatoms selected from
the group consisting of O, N, Si and S, and wherein the nitrogen and
sulfur atoms are optionally oxidized and the nitrogen heteroatom can
optionally be quaternized. The heteroatom(s) O, N and S may be placed at
any interior position of the heteroalkyl group. The heteroatom Si can be
placed at any position of the heteroalkyl group, including the position
at which the alkyl group is attached to the remainder of the molecule.
The heteroatom O, N, or S cannot be placed at the position at which the
alkyl group is attached to the remainder of the molecule. The heteroatom
O, N, or S can be placed at the external position distal to where the
alkyl group is attached to the remainder of the molecule. Examples
include --CH2--CH2--O--CH3,
--CH2--CH2--NH--CH3,
--CH2--CH2--N(CH3)--CH3,
--CH2--S--CH2--CH3, --CH2--CH2--S(O)--CH3,
--CH2--CH2--S(O)2--CH3, --CH═CH--O--CH3,
--Si(CH3)3, --CH2--CH═N--OCH3, and
--CH═CH--N(CH3)--CH3. Up to two heteroatoms can be
consecutive, such as, for example, --CH2--NH--OCH3 and
--CH2--O--Si(CH3)3. Also included in the term
"heteroalkyl" are those radicals described as "heteroalkylene" and
"heterocycloalkyl." The term "heteroalkylene" by itself or as part of
another substituent means a divalent radical derived from heteroalkyl, as
exemplified by --CH2--CH2--S--CH2--CH2-- and
--CH2--S--CH2--CH2--NH--CH2--. Still further, for
heteroalkylene linking groups, as well as all other linking group
provided herein, no orientation of the linking group is implied.

[0027] As used herein, and unless otherwise specified, the term "aryl"
refers to a monocyclic aromatic group and/or multicyclic monovalent
aromatic group that contain at least one aromatic hydrocarbon ring. In
certain embodiments, the aryl has from 6 to 20 (C6-20), from 6 to 15
(C6-15), or from 6 to 10 (C6-10) ring atoms. Examples of aryl
groups include, but are not limited to, phenyl, naphthyl, fluorenyl,
azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl, and terphenyl. Aryl
also refers to bicyclic or tricyclic carbon rings, where one of the rings
is aromatic and the others of which may be saturated, partially
unsaturated, or aromatic, for example, dihydronaphthyl, indenyl, indanyl,
or tetrahydronaphthyl (tetralinyl). In certain embodiments, aryl may also
be optionally substituted with one or more substituents.

[0028] As used herein, and unless otherwise specified, the term
"arylalkyl" or "aralkyl" refers to a monovalent alkyl group substituted
with aryl. In certain embodiments, both alkyl and aryl may be optionally
substituted with one or more substituents.

[0029] As used herein, and unless otherwise specified, the term
"heteroaryl" refers to a monocyclic aromatic group and/or multicyclic
aromatic group that contain at least one aromatic ring, wherein at least
one ring contains one or more heteroatoms independently selected from O,
S, and N. Each ring of a heteroaryl group can contain one or two O atoms,
one or two S atoms, and/or one to four N atoms, provided that the total
number of heteroatoms in each ring is four or less and each ring contains
at least one carbon atom. In certain embodiments, the heteroaryl has from
5 to 20, from 5 to 15, or from 5 to 10 ring atoms. Examples of monocyclic
heteroaryl groups include, but are not limited to, furanyl, imidazolyl,
isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl,
pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl,
thienyl, tetrazolyl, triazinyl, and triazolyl. Examples of bicyclic
heteroaryl groups include, but are not limited to, benzofuranyl,
benzimidazolyl, benzoisoxazolyl, benzopyranyl, benzothiadiazolyl,
benzothiazolyl, benzothienyl, benzothiophenyl, benzotriazolyl,
benzoxazolyl, furopyridyl, imidazopyridinyl, imidazothiazolyl,
indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothienyl,
isoindolyl, isoquinolinyl, isothiazolyl, naphthyridinyl,
oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridyl,
pyrrolopyridyl, quinolinyl, quinoxalinyl, quinazolinyl,
thiadiazolopyrimidyl, and thienopyridyl. Examples of tricyclic heteroaryl
groups include, but are not limited to, acridinyl, benzindolyl,
carbazolyl, dibenzofuranyl, perimidinyl, phenanthrolinyl,
phenanthridinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl,
and xanthenyl. In certain embodiments, heteroaryl may be optionally
substituted with one or more substituents.

[0030] As used herein, and unless otherwise specified, the term
"heterocyclyl," "heterocycloalkyl," or "heterocyclic" refers to a
monocyclic non-aromatic ring system and/or multicyclic ring system that
contains at least one non-aromatic ring, wherein at least one ring
contains one or more heteroatoms independently selected from O, S, or N;
and the remaining ring atoms are carbon atoms. In certain embodiments,
the heterocyclyl or heterocyclic group has from 3 to 20, from 3 to 15,
from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6 ring atoms. In
certain embodiments, the heterocyclyl is a monocyclic, bicyclic,
tricyclic, or tetracyclic ring system, which may include a fused or
bridged ring system, and in which the nitrogen or sulfur atoms may be
optionally oxidized, the nitrogen atoms may be optionally quaternized,
and some rings may be partially or fully saturated, or aromatic. The
heterocyclyl may be attached to the main structure at any heteroatom or
carbon atom which results in the creation of a stable compound. Examples
of such heterocyclic radicals include, but are not limited to, azepinyl,
benzodioxanyl, benzodioxolyl, benzofuranonyl, benzopyranonyl,
benzopyranyl, benzotetrahydrofuranyl, benzotetrahydrothienyl,
benzothiopyranyl, benzoxazinyl, β-carbolinyl, chromanyl, chromonyl,
cinnolinyl, coumarinyl, decahydroisoquinolinyl, dihydrobenzisothiazinyl,
dihydrobenzisoxazinyl, dihydrofuryl, dihydroisoindolyl, dihydropyranyl,
dihydropyrazolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl,
dihydropyrrolyl, dioxolanyl, 1,4-dithianyl, furanonyl, imidazolidinyl,
imidazolinyl, indolinyl, isobenzotetrahydrofuranyl,
isobenzotetrahydrothienyl, isochromanyl, isocoumarinyl, isoindolinyl,
isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl,
octahydroisoindolyl, oxazolidinonyl, oxazolidinyl, oxiranyl, piperazinyl,
piperidinyl, 4-piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl,
pyrrolinyl, quinuclidinyl, tetrahydrofuryl, tetrahydroisoquinolinyl,
tetrahydropyranyl, tetrahydrothienyl, thiamorpholinyl, thiazolidinyl,
tetrahydroquinolinyl, and 1,3,5-trithianyl. In certain embodiments,
heterocyclic may be optionally substituted with one or more substituents.

[0031] As used herein, and unless otherwise specified, the term "halogen",
"halide" or "halo" refers to fluorine, chlorine, bromine, and/or iodine.

[0036] As used herein, and unless otherwise specified, the term "hydrate"
means a compound provided herein or a salt thereof, which further
includes a stoichiometric or non-stoichiometric amount of water bound by
non-covalent intermolecular forces.

[0037] As used herein, and unless otherwise specified, the term "solvate"
refers to a compound provided herein or a salt thereof, which further
includes a stoichiometric or non-stoichiometric amount of solvent bound
by non-covalent intermolecular forces. Where the solvent is water, the
solvate is a hydrate (e.g., mono-hydrate, dihydrate, trihydrate,
tetrahydrate and the like).

[0038] As used herein, and unless otherwise specified, the term
"stereoisomer" encompasses all enantiomerically/stereomerically pure and
enantiomerically/stereomerically enriched compounds provided herein.

[0039] As used herein and unless otherwise specified, the term
"stereomerically pure" means a composition that comprises one
stereoisomer of a compound and is substantially free of other
stereoisomers of that compound. For example, a stereomerically pure
composition of a compound having one chiral center will be substantially
free of the opposite enantiomer of the compound. A stereomerically pure
composition of a compound having two chiral centers will be substantially
free of other diastereomers of the compound. A typical stereomerically
pure compound comprises greater than about 80% by weight of one
stereoisomer of the compound and less than about 20% by weight of other
stereoisomers of the compound, greater than about 90% by weight of one
stereoisomer of the compound and less than about 10% by weight of the
other stereoisomers of the compound, greater than about 95% by weight of
one stereoisomer of the compound and less than about 5% by weight of the
other stereoisomers of the compound, greater than about 97% by weight of
one stereoisomer of the compound and less than about 3% by weight of the
other stereoisomers of the compound, or greater than about 99% by weight
of one stereoisomer of the compound and less than about 1% by weight of
the other stereoisomers of the compound.

[0040] As used herein and unless otherwise indicated, the term
"stereomerically enriched" means a composition that comprises greater
than about 55% by weight of one stereoisomer of a compound, greater than
about 60% by weight of one stereoisomer of a compound, greater than about
70% by weight, or greater than about 80% by weight of one stereoisomer of
a compound.

[0041] As used herein, and unless otherwise indicated, the term
"enantiomerically pure" means a stereomerically pure composition of a
compound having one chiral center. Similarly, the term "enantiomerically
enriched" means a stereomerically enriched composition of a compound
having one chiral center.

[0042] In certain embodiments, as used herein, and unless otherwise
specified, "optically active" and "enantiomerically active" refer to a
collection of molecules, which has an enantiomeric excess of no less than
about 50%, no less than about 70%, no less than about 80%, no less than
about 90%, no less than about 91%, no less than about 92%, no less than
about 93%, no less than about 94%, no less than about 95%, no less than
about 96%, no less than about 97%, no less than about 98%, no less than
about 99%, no less than about 99.5%, or no less than about 99.8%. In
certain embodiments, the compound comprises about 95% or more of the
desired enantiomer and about 5% or less of the less preferred enantiomer
based on the total weight of the racemate in question.

[0043] In describing an optically active compound, the prefixes R and S
are used to denote the absolute configuration of the molecule about its
chiral center(s). The (+) and (-) are used to denote the optical rotation
of the compound, that is, the direction in which a plane of polarized
light is rotated by the optically active compound. The (-) prefix
indicates that the compound is levorotatory, that is, the compound
rotates the plane of polarized light to the left or counterclockwise. The
(+) prefix indicates that the compound is dextrorotatory, that is, the
compound rotates the plane of polarized light to the right or clockwise.
However, the sign of optical rotation, (+) or (-), is not related to the
absolute configuration of the molecule, R or S.

[0044] As used herein, and unless otherwise specified, the terms
"composition," "formulation," and "dosage form" are intended to encompass
products comprising the specified ingredient(s) (in the specified
amounts, if indicated), as well as any product(s) which result, directly
or indirectly, from combination of the specified ingredient(s) in the
specified amount(s).

[0045] As used herein, and unless otherwise specified, the term
"pharmaceutically acceptable carrier," "pharmaceutically acceptable
excipient," "physiologically acceptable carrier," or "physiologically
acceptable excipient" refers to a pharmaceutically-acceptable material,
composition, or vehicle, such as a liquid or solid filler, diluent,
excipient, solvent, or encapsulating material. In one embodiment, each
component is "pharmaceutically acceptable" in the sense of being
compatible with the other ingredients of a pharmaceutical formulation,
and suitable for use in contact with the tissue or organ of humans and
animals without excessive toxicity, irritation, allergic response,
immunogenicity, or other problems or complications, commensurate with a
reasonable benefit/risk ratio. In one embodiment, by "pharmaceutical" or
"pharmaceutically acceptable" it is meant that any diluent(s),
excipient(s) or carrier(s) in the composition, formulation, or dosage
form are compatible with the other ingredient(s) and not deleterious to
the recipient thereof. See, e.g., Remington: The Science and Practice of
Pharmacy, 21st Edition, Lippincott Williams & Wilkins: Philadelphia, Pa.,
2005; Handbook of Pharmaceutical Excipients, 5th Edition, Rowe et al.,
Eds., The Pharmaceutical Press and the American Pharmaceutical
Association: 2005; and Handbook of Pharmaceutical Additives, 3rd Edition,
Ash and Ash Eds., Gower Publishing Company: 2007; Pharmaceutical
Preformulation and Formulation, 2nd Edition, Gibson Ed., CRC Press LLC:
Boca Raton, Fla., 2009.

[0046] As used herein, and unless otherwise specified, the terms "active
ingredient" and "active substance" refer to a compound, which is
administered, alone or in combination with one or more pharmaceutically
acceptable excipients, to a subject for treating, preventing, managing,
or ameliorating one or more symptoms of a condition, disorder, or
disease. As used herein, "active ingredient" and "active substance" may
be an optically active isomer of a compound described herein.

[0047] As used herein, and unless otherwise specified, the terms "drug,"
"therapeutic agent," and "chemotherapeutic agent" refer to a compound, or
a pharmaceutical composition thereof, which is administered to a subject
for treating, preventing, managing, or ameliorating one or more symptoms
of a condition, disorder, or disease.

[0048] As used herein, and unless otherwise indicated, the terms "treat,"
"treating" and "treatment" refer to the eradication or amelioration of a
disease or disorder, or of one or more symptoms associated with the
disease or disorder. In certain embodiments, the terms refer to
minimizing the spread or worsening of the disease or disorder resulting
from the administration of one or more prophylactic or therapeutic agents
to a subject with such a disease or disorder. In some embodiments, the
terms refer to the administration of a compound or dosage form provided
herein, with or without one or more additional active agent(s), after the
diagnosis or onset of symptoms of the particular disease.

[0049] As used herein, and unless otherwise indicated, the terms
"prevent," "preventing" and "prevention" refer to the prevention of the
onset, recurrence or spread of a disease or disorder, or of one or more
symptoms thereof. In certain embodiments, the terms refer to the
treatment with or administration of a compound or dosage form provided
herein, with or without one or more other additional active agent(s),
prior to the onset of symptoms, particularly to patients at risk of
disease or disorders provided herein. The terms encompass the inhibition
or reduction of a symptom of the particular disease. In certain
embodiments, subjects with familial history of a disease are potential
candidates for preventive regimens. In certain embodiments, subjects who
have a history of recurring symptoms are also potential candidates for
the prevention. In this regard, the term "prevention" may be
interchangeably used with the term "prophylactic treatment."

[0050] As used herein, and unless otherwise specified, the terms "manage,"
"managing" and "management" refer to preventing or slowing the
progression, spread or worsening of a disease or disorder, or of one or
more symptoms thereof. Often, the beneficial effects that a subject
derives from a prophylactic and/or therapeutic agent do not result in a
cure of the disease or disorder. In this regard, the term "managing"
encompasses treating a patient who had suffered from the particular
disease in an attempt to prevent or minimize the recurrence of the
disease.

[0051] As used herein, and unless otherwise specified, "amelioration" of
the symptoms of a particular disorder by administration of a particular
pharmaceutical composition refers to any lessening, whether permanent or
temporary, lasting or transient, that can be attributed to or associated
with the administration of the composition.

[0052] As used herein, and unless otherwise specified, the term
"therapeutically effective amount" or "effective amount" of a compound
means an amount sufficient to provide a therapeutic benefit in the
treatment or management of a disease or disorder, or to delay or minimize
one or more symptoms associated with the disease or disorder. A
"therapeutically effective amount" or "effective amount" of a compound
means an amount of therapeutic agent, alone or in combination with one or
more other therapies, which provides a therapeutic benefit in the
treatment or management of the disease or disorder. The term
"therapeutically effective amount" and "effective amount" can encompass
an amount that improves overall therapy, reduces, delays, or avoids
symptoms or causes of disease or disorder, or enhances the therapeutic
efficacy of another therapeutic agent.

[0053] As used herein, and unless otherwise specified, a "prophylactically
effective amount" of a compound is an amount sufficient to prevent a
disease or disorder, or prevent its recurrence. A prophylactically
effective amount of a compound means an amount of therapeutic agent,
alone or in combination with one or more other therapies, which provides
a prophylactic benefit in the prevention of the disease. The term
"prophylactically effective amount" can encompass an amount that improves
overall prophylaxis or enhances the prophylactic efficacy of another
prophylactic agent.

[0054] As used herein, and unless otherwise specified, the term "subject"
is defined herein to include animals such as mammals, including, but not
limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs,
cats, rabbits, rats, mice and the like. In specific embodiments, the
subject is a human. The terms "subject" and "patient" are used
interchangeably herein in reference, for example, to a mammalian subject,
such as a human.

[0055] As used herein, and unless otherwise specified, "tumor" refers to
all neoplastic cell growth and proliferation, whether malignant or
benign, and all pre-cancerous and cancerous cells and tissues. As used
herein, and unless otherwise specified, "neoplastic" refers to any form
of dysregulated or unregulated cell growth, whether malignant or benign,
resulting in abnormal tissue growth. Thus, "neoplastic cells" include
malignant and benign cells having dysregulated or unregulated cell
growth.

[0056] As used herein, and unless otherwise specified, the terms "cancer"
and "cancerous" refer to or describe the physiological condition in
mammals that is typically characterized by unregulated cell growth.
Examples of cancer include, but are not limited to, lymphoma, leukemia,
and solid tumors, such as, for example, lung cancer.

[0057] As used herein, and unless otherwise specified, the term
"proliferative" disorder or disease refers to unwanted cell proliferation
of one or more subset of cells in a multicellular organism resulting in
harm (i.e., discomfort or decreased life expectancy) to the multicellular
organism. For example, as used herein, proliferative disorder or disease
includes neoplastic disorders and other proliferative disorders.

[0058] As used herein, and unless otherwise specified, the term "triple
negative breast cancer" refers to specific subtypes of breast cancer that
are negative clinically for the expression of estrogen receptor (ER),
progesterone receptor (PR) and human epidermal growth factor receptor 2
(HER2) protein. These subtypes of breast cancer are generally diagnosed
based upon the presence or the lack of three receptors known to fuel most
breast cancers: estrogen receptors, progesterone receptors and human
epidermal growth factor receptor 2. None of these receptors are found in
patients diagnosed with triple negative breast cancer. In other words, a
triple negative breast cancer diagnosis means that the offending tumor is
estrogen receptor-negative, progesterone receptor-negative and
HER2-negative.

[0059] As used herein, and unless otherwise specified, the term "relapsed"
refers to a situation where a subject, that has had a remission of cancer
after a therapy, has a return of cancer cells.

[0060] As used herein, and unless otherwise specified, the term
"refractory" or "resistant" refers to a circumstance where a subject,
even after intensive treatment, has residual cancer cells in the body.

[0061] As used herein, and unless otherwise specified, the term "drug
resistance" refers to the condition when a disease does not respond to
the treatment of a drug or drugs. Drug resistance can be either
intrinsic, which means the disease has never been responsive to the drug
or drugs, or it can be acquired, which means the disease ceases
responding to a drug or drugs that the disease had previously responded
to. In certain embodiments, drug resistance is intrinsic. In certain
embodiments, the drug resistance is acquired.

[0064] In one embodiment, provided herein is a compound of formula (I):

##STR00002##

or an enantiomer, a mixture of enantiomers, or a mixture of two or more
diastereomers thereof; or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof; wherein:

[0065] (A) L is S(O)2;

[0066] R1 is phenyl or (5 to 6
membered)heteroaryl, each of which is optionally substituted with one or
more halogen, cyano, R2, OR5, OC(O)R5, C(O)R5,
C(O)OR5, C(O)NR5R6, NR5C(O)R6, NR5R6,
OS(O)R5, SR5, S(O)R5, S(O)2R5,
S(O)2NR5R6, or NR5S(O)2R6;

[0072] R5 and R6 are each
independently hydrogen, (C1-C8)alkyl, (C2-C8)
alkenyl, (C2-C8)alkynyl, (C1-C8)heteroalkyl,
(C3-C8)cycloalkyl, (C7-C12)aralkyl, phenyl, (5 to 6
membered)heteroaryl, or (3 to 7 membered)heterocyclyl; or R5 and
R6 together form a 3 to 10 membered ring; or

[0073] (B) L is C(O);

[0074] R1 is phenyl or (5 to 6
membered)heteroaryl, each of which is optionally substituted with one or
more halogen, cyano, R2, OR5, OC(O)R5, C(O)R5,
C(O)OR5, C(O)NR5R6, NR5C(O)R6, NR5R6,
OS(O)R5, SR5, S(O)R5, S(O)2R5,
S(O)2NR5R6, or NR5S(O)2R6;

[0079] wherein (i) each X is independently N or CH; and R7 and
R8 are each independently halogen or CF3; (ii) R9 is
chloro or CF3; R10 is fluoro, chloro, or CF3; and R11
is hydrogen, fluoro, chloro, CF3, or (C1-C4)alkyl;

[0080] R5 and R6 are each independently hydrogen,
(C1-C8)alkyl, (C2-C8) alkenyl,
(C2-C8)alkynyl, (C1-C8)heteroalkyl,
(C3-C8)cycloalkyl, (C7-C12)aralkyl, phenyl, (5 to 6
membered)heteroaryl, or (3 to 7 membered)heterocyclyl; or R5 and
R6 together form a 3 to 10 membered ring; and

[0081] (i) when
R7 and R8 are both CF3 and X is CH, R1 is not
3,4-dichlorophenyl or 3,5-dichlorophenyl; and (ii) when R9 and
R10 are both CF3 and R11 is hydrogen, R1 is not
3,4-dichlorophenyl or 3,5-dichlorophenyl.

[0082] In one embodiment, provided herein is a compound of formula (I):

##STR00004##

or an enantiomer, a mixture of enantiomers, or a mixture of two or more
diastereomers thereof; or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof; wherein:

[0083] (A) L is S(O)2;

[0084] R1 is phenyl or (5 to 6
membered)heteroaryl, each of which is optionally substituted with one or
more halogen, cyano, R2, OR5, OC(O)R5, C(O)R5,
C(O)OR5, C(O)NR5R6, NR5C(O)R6, NR5R6,
OS(O)R5, SR5, S(O)R5, S(O)2R5,
S(O)2NR5R6, or NR5S(O)2R6;

[0090] R5 and R6 are each
independently hydrogen, (C1-C8)alkyl, (C2-C8)
alkenyl, (C2-C8)alkynyl, (C1-C8)heteroalkyl,
(C3-C8)cycloalkyl, (C7-C12)aralkyl, phenyl, (5 to 6
membered)heteroaryl, or (3 to 7 membered)heterocyclyl; or R5 and
R6 together form a 3 to 10 membered ring; or

[0091] (B) L is C(O);

[0092] R1 is phenyl or (5 to 6
membered)heteroaryl, each of which is optionally substituted with one or
more halogen, cyano, R2, OR5, OC(O)R5, C(O)R5,
C(O)OR5, C(O)NR5R6, NR5C(O)R6, NR5R6,
OS(O)R5, SR5, S(O)R5, S(O)2R5,
S(O)2NR5R6, or NR5S(O)2R6;

[0097] wherein each X is independently N or CH; and R7 and R8
are each independently halogen or CF3;

[0098] R5 and R6
are each independently hydrogen, (C1-C8)alkyl,
(C2-C8) alkenyl, (C2-C8)alkynyl,
(C1-C8)heteroalkyl, (C3-C8)cycloalkyl,
(C7-C12)aralkyl, phenyl, (5 to 6 membered)heteroaryl, or (3 to
7 membered)heterocyclyl; or R5 and R6 together form a 3 to 10
membered ring; and

[0099] when R7 and R8 are both CF3,
R1 is not 3,4-dichlorophenyl or 3,5-dichlorophenyl.

[0100] In one embodiment, provided herein is a compound of formula (II):

##STR00006##

or an enantiomer, a mixture of enantiomers, or a mixture of two or more
diastereomers thereof; or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof; wherein:

[0101] R1 is phenyl or (5 to
6 membered)heteroaryl, each of which is optionally substituted with one
or more halogen, cyano, R2, OR5, OC(O)R5, C(O)R5,
C(O)OR5, C(O)NR5R6, NR5C(O)R6, NR5R6,
OS(O)R5, SR5, S(O)R5, S(O)2R5,
S(O)2NR5R6, or NR5S(O)2R6;

[0107] R5 and R6 are each
independently hydrogen, (C1-C8)alkyl, (C2-C8)
alkenyl, (C2-C8)alkynyl, (C1-C8)heteroalkyl,
(C3-C8)cycloalkyl, (C7-C12)aralkyl, phenyl, (5 to 6
membered)heteroaryl, or (3 to 7 membered)heterocyclyl; or R5 and
R6 together form a 3 to 10 membered ring.

[0108] In one embodiment, provided herein is a compound of formula (II),
or an enantiomer, a mixture of enantiomers, or a mixture of two or more
diastereomers thereof; or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof;

wherein:

[0109] R1 is phenyl or (5 to 6 membered)heteroaryl, each
of which is optionally substituted with one or more halogen, cyano,
R2, OR5, OC(O)R5, C(O)R5, C(O)OR5,
C(O)NR5R6, NR5C(O)R6, NR5R6, OS(O)R5,
SR5, S(O)R5, S(O)2R5, S(O)2NR5R6, or
NR5S(O)2R6;

[0114] wherein each X is independently N or CH; and R7 and R8
are each independently halogen or CF3; and

[0115] R5 and
R6 are each independently hydrogen, (C1-C8)alkyl,
(C2-C8) alkenyl, (C2-C8)alkynyl,
(C1-C8)heteroalkyl, (C3-C8)cycloalkyl,
(C7-C12)aralkyl, phenyl, (5 to 6 membered)heteroaryl, or (3 to
7 membered)heterocyclyl; or R5 and R6 together form a 3 to 10
membered ring.

[0116] In one embodiment, provided herein is a compound of formula (III):

##STR00008##

or an enantiomer, a mixture of enantiomers, or a mixture of two or more
diastereomers thereof; or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof; wherein:

[0117] R1 is phenyl or (5 to
6 membered)heteroaryl, each of which is optionally substituted with one
or more halogen, cyano, R2, OR5, OC(O)R5, C(O)R5,
C(O)OR5, C(O)NR5R6, NR5C(O)R6, NR5R6,
OS(O)R5, SR5, S(O)R5, S(O)2R5,
S(O)2NR5R6, or NR5S(O)2R6;

[0122] R5 and R6 are each independently
hydrogen, (C1-C8)alkyl, (C2-C8) alkenyl,
(C2-C8)alkynyl, (C1-C8)heteroalkyl,
(C3-C8)cycloalkyl, (C7-C12)aralkyl, phenyl, (5 to 6
membered)heteroaryl, or (3 to 7 membered)heterocyclyl; or R5 and
R6 together form a 3 to 10 membered ring;

[0123] R7 and R8
are each independently halogen or CF3;

[0124] each X is
independently N or CH; and

[0125] when R7 and R8 are both
CF3 and X is CH, R1 is not 3,4-dichlorophenyl or
3,5-dichlorophenyl.

[0126] In one embodiment, provided herein is a compound of formula (IV):

##STR00009##

or an enantiomer, a mixture of enantiomers, or a mixture of two or more
diastereomers thereof; or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof; wherein:

[0127] R1 is phenyl or (5 to
6 membered)heteroaryl, each of which is optionally substituted with one
or more halogen, cyano, R2, OR5, OC(O)R5, C(O)R5,
C(O)OR5, C(O)NR5R6, NR5C(O)R6, NR5R6,
OS(O)R5, SR5, S(O)R5, S(O)2R5,
S(O)2NR5R6, or NR5S(O)2R6;

[0132] R5 and R6 are each independently
hydrogen, (C1-C8)alkyl, (C2-C8) alkenyl,
(C2-C8)alkynyl, (C1-C8)heteroalkyl,
(C3-C8)cycloalkyl, (C7-C12)aralkyl, phenyl, (5 to 6
membered)heteroaryl, or (3 to 7 membered)heterocyclyl; or R5 and
R6 together form a 3 to 10 membered ring;

[0133] R9 is chloro
or CF3;

[0134] R10 is fluoro, chloro, or CF3;

[0135]
R11 is hydrogen, fluoro, chloro, CF3, or
(C1-C4)alkyl; and

[0136] when R9 and R10 are both
CF3 and R11 is hydrogen, R1 is not 3,4-dichlorophenyl or
3,5-dichlorophenyl.

[0137] In one embodiment, provided herein is a compound of formula (V):

##STR00010##

or an enantiomer, a mixture of enantiomers, or a mixture of two or more
diastereomers thereof; or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof; wherein:

[0142] R5 and R6 are each independently
hydrogen, (C1-C8)alkyl, (C2-C8) alkenyl,
(C2-C8)alkynyl, (C1-C8)heteroalkyl,
(C3-C8)cycloalkyl, (C7-C12)aralkyl, phenyl, (5 to 6
membered)heteroaryl, or (3 to 7 membered)heterocyclyl; or R5 and
R6 together form a 3 to 10 membered ring;

[0143] R9 is chloro
or CF3;

[0144] R10 is fluoro, chloro, or CF3;

[0145]
R11 is hydrogen, fluoro, chloro, CF3, or
(C1-C4)alkyl;

[0146] R12 is fluoro, chloro, bromo, methyl,
hydroxyl, or methoxyl,

[0147] n is 0, 1, or 2; and

[0148] when R9
and R10 are both CF3, R11 is hydrogen, and n is 2; then
R12 is not chloro.

[0149] In one embodiment, when R9 and R10 are both CF3 and
R11 is hydrogen and n is 2, then R12 is not chloro.

[0150] In one embodiment, when R9 and R10 are both CF3 and
R11 is hydrogen, then R12 is not chloro.

[0151] In one embodiment, R9 and R10 are both CF3, R11
is hydrogen, R12 is chloro, and n is 1.

[0152] In one embodiment, R12 is fluoro, bromo, methyl, hydroxyl, or
methoxyl.

[0158] In one embodiment, R1 is phenyl optionally substituted with
one or more halogen, hydroxyl, (C1-C6)alkyl,
O(C1-C6)alkyl, or O(C3-C6)cycloalkyl. In one
embodiment, R1 is phenyl optionally substituted with one to three
halogen, hydroxyl, (C1-C6)alkyl, O(C1-C6)alkyl, or
O(C3-C6)cycloalkyl. In one embodiment, R1 is phenyl
optionally substituted with one or more halogen, hydroxyl,
(C1-C4)alkyl, O(C1-C4)alkyl, or
O(C3-C4)cycloalkyl. In one embodiment, R1 is phenyl
optionally substituted with one to three halogen, hydroxyl,
(C1-C4)alkyl, O(C1-C4)alkyl, or
O(C3-C4)cycloalkyl. In particular embodiments, R1 is
phenyl optionally substituted with one or more fluoro, chloro, bromo,
hydroxyl, methyl, methoxyl, ethoxyl, propoxyl, isopropoxyl,
cyclopropoxyl, butoxyl, or isobutoxyl. In particular embodiments, R1
is phenyl optionally substituted with one to three fluoro, chloro, bromo,
hydroxyl, methyl, methoxyl, ethoxyl, propoxyl, isopropoxyl,
cyclopropoxyl, butoxyl, or isobutoxyl.

[0159] In one embodiment, R1 is phenyl substituted with one or more
halogen, hydroxyl, (C1-C6)alkyl, O(C1-C6)alkyl, or
O(C3-C6)cycloalkyl. In one embodiment, R1 is phenyl
substituted with one to three halogen, hydroxyl, (C1-C6)alkyl,
O(C1-C6)alkyl, or O(C3-C6) cycloalkyl. In one
embodiment, R1 is phenyl substituted with one or more halogen,
hydroxyl, (C1-C4)alkyl, O(C1-C4)alkyl, or
O(C3-C4)cycloalkyl. In one embodiment, R1 is phenyl
substituted with one to three halogen, hydroxyl, (C1-C4)alkyl,
O(C1-C4)alkyl, or O(C3-C4) cycloalkyl. In particular
embodiments, R1 is phenyl substituted with one or more fluoro,
chloro, bromo, hydroxyl, methyl, methoxyl, ethoxyl, propoxyl,
isopropoxyl, cyclopropoxyl, butoxyl, or isobutoxyl. In particular
embodiments, R1 is phenyl substituted with one to three fluoro,
chloro, bromo, hydroxyl, methyl, methoxyl, ethoxyl, propoxyl,
isopropoxyl, cyclopropoxyl, butoxyl, or isobutoxyl.

[0160] In one embodiment, R1 is phenyl substituted with one or more
fluoro, chloro, bromo, hydroxyl, (C1-C6)alkyl,
O(C1-C6)alkyl, or O(C3-C6)cycloalkyl. In one
embodiment, R1 is phenyl substituted with one or more fluoro, bromo,
hydroxyl, (C1-C6)alkyl, O(C1-C6)alkyl, or
O(C3-C6)cycloalkyl. In one embodiment, R1 is phenyl
substituted with one to three fluoro, chloro, bromo, hydroxyl,
(C1-C6)alkyl, O(C1-C6)alkyl, or
O(C3-C6)cycloalkyl. In one embodiment, R1 is phenyl
substituted with one to three fluoro, bromo, hydroxyl,
(C1-C6)alkyl, O(C1-C6)alkyl, or O(C3-C6)
cycloalkyl. In one embodiment, R1 is phenyl substituted with one or
more fluoro, chloro, bromo, hydroxyl, (C1-C4)alkyl,
O(C1-C4)alkyl, or O(C3-C4)cycloalkyl. In one
embodiment, R1 is phenyl substituted with one or more fluoro, bromo,
hydroxyl, (C1-C4)alkyl, O(C1-C4)alkyl, or
O(C3-C4)cycloalkyl. In one embodiment, R1 is phenyl
substituted with one to three fluoro, chloro, bromo, hydroxyl,
(C1-C4)alkyl, O(C1-C4)alkyl, or O(C3-C4)
cycloalkyl. In one embodiment, R1 is phenyl substituted with one to
three fluoro, bromo, hydroxyl, (C1-C4)alkyl,
O(C1-C4)alkyl, or O(C3-C4) cycloalkyl. In particular
embodiments, R1 is phenyl substituted with one or more fluoro,
chloro, bromo, hydroxyl, methyl, methoxyl, ethoxyl, propoxyl,
isopropoxyl, cyclopropoxyl, butoxyl, or isobutoxyl. In particular
embodiments, R1 is phenyl substituted with one or more fluoro,
bromo, hydroxyl, methyl, methoxyl, ethoxyl, propoxyl, isopropoxyl,
cyclopropoxyl, butoxyl, or isobutoxyl. In particular embodiments, R1
is phenyl substituted with one to three fluoro, chloro, bromo, hydroxyl,
methyl, methoxyl, ethoxyl, propoxyl, isopropoxyl, cyclopropoxyl, butoxyl,
or isobutoxyl. In particular embodiments, R1 is phenyl substituted
with one to three fluoro, bromo, hydroxyl, methyl, methoxyl, ethoxyl,
propoxyl, isopropoxyl, cyclopropoxyl, butoxyl, or isobutoxyl.

[0161] In one embodiment, R1 is phenyl substituted with one or more
hydroxyl, (C1-C6)alkyl, O(C1-C6)alkyl, or
O(C3-C6)cycloalkyl. In one embodiment, R1 is phenyl
substituted with one to three hydroxyl, (C1-C6)alkyl,
O(C1-C6)alkyl, or O(C3-C6) cycloalkyl. In one
embodiment, R1 is phenyl substituted with one or more hydroxyl,
(C1-C4)alkyl, O(C1-C4)alkyl, or
O(C3-C4)cycloalkyl. In one embodiment, R1 is phenyl
substituted with one to three hydroxyl, (C1-C4)alkyl,
O(C1-C4)alkyl, or O(C3-C4) cycloalkyl. In particular
embodiments, R1 is phenyl substituted with one or more hydroxyl,
methyl, methoxyl, ethoxyl, propoxyl, isopropoxyl, cyclopropoxyl, butoxyl,
or isobutoxyl. In particular embodiments, R1 is phenyl substituted
with one to three hydroxyl, methyl, methoxyl, ethoxyl, propoxyl,
isopropoxyl, cyclopropoxyl, butoxyl, or isobutoxyl.

[0162] In one embodiment, R1 is (5 to 6 membered)heteroaryl
optionally substituted with one or more halogen, hydroxyl,
(C1-C6)alkyl, O(C1-C6)alkyl, or O(C3-C6)
cycloalkyl. In one embodiment, R1 is (5 to 6 membered)heteroaryl
optionally substituted with one to three halogen, hydroxyl,
(C1-C6)alkyl, O(C1-C6)alkyl, or
O(C3-C6)cycloalkyl. In one embodiment, R1 is (5 to 6
membered)heteroaryl optionally substituted with one or more halogen,
hydroxyl, (C1-C4)alkyl, O(C1-C4)alkyl, or
O(C3-C4)cycloalkyl. In one embodiment, R1 is (5 to 6
membered)heteroaryl optionally substituted with one to three halogen,
hydroxyl, (C1-C4)alkyl, O(C1-C4)alkyl, or
O(C3-C4)cycloalkyl. In particular embodiments, R1 is (5 to
6 membered)heteroaryl optionally substituted with one or more fluoro,
chloro, bromo, hydroxyl, methyl, methoxyl, ethoxyl, propoxyl,
isopropoxyl, cyclopropoxyl, butoxyl, or isobutoxyl. In particular
embodiments, R1 is (5 to 6 membered)heteroaryl optionally
substituted with one to three fluoro, chloro, bromo, hydroxyl, methyl,
methoxyl, ethoxyl, propoxyl, isopropoxyl, cyclopropoxyl, butoxyl, or
isobutoxyl.

[0163] In one embodiment, R1 is phenyl optionally substituted with
one or two fluoro, chloro, bromo, methyl, hydroxyl, or methoxyl. In one
embodiment, R1 is phenyl optionally substituted with one substituent
selected from fluoro, chloro, bromo, methyl, hydroxyl, and methoxyl. In
specific embodiments, R1 is phenyl. In specific embodiments, R1
is phenyl optionally substituted with fluoro, chloro, or bromo. In
specific embodiments, R1 is phenyl optionally substituted with
fluoro, chloro, bromo, or methoxyl. In specific embodiments, R1 is
phenyl optionally substituted with fluoro, chloro, or bromo at the
4-position. In specific embodiments, R1 is phenyl optionally
substituted with fluoro, chloro, bromo, or methoxyl at the 4-position.

[0164] In one embodiment, R2 is (C1-C8)alkyl optionally
substituted with one or more optionally substituted aryl. In one
embodiment, R2 is (C1-C6)alkyl optionally substituted with
one or more optionally substituted aryl. In one embodiment, R2 is
(C1-C4)alkyl optionally substituted with one or more optionally
substituted aryl. In one embodiment, R2 is (C1-C8)alkyl
optionally substituted with one or more optionally substituted
heteroaryl. In one embodiment, R2 is (C1-C6)alkyl
optionally substituted with one or more optionally substituted
heteroaryl. In one embodiment, R2 is (C1-C4)alkyl
optionally substituted with one or more optionally substituted
heteroaryl. In one embodiment, R2 is (C1-C8)alkyl
optionally substituted with one or more optionally substituted
heterocyclyl. In one embodiment, R2 is (C1-C6)alkyl
optionally substituted with one or more optionally substituted
heterocyclyl. In one embodiment, R2 is (C1-C4)alkyl
optionally substituted with one or more optionally substituted
heterocyclyl. In one embodiment, R2 is (C1-C8)alkyl
optionally substituted with one or more halogen. In one embodiment,
R2 is (C1-C6)alkyl optionally substituted with one or more
halogen. In one embodiment, R2 is (C1-C4)alkyl optionally
substituted with one or more halogen. In one embodiment, the alkyl is
optionally substituted with one or more fluoro. In one embodiment,
R2 is CH3 or CF3. In one embodiment, R2 is
(C1-C4)alkyl optionally substituted with one or more fluoro or
optionally substituted phenyl. In one embodiment, R2 is (i)
(C1-C4)alkyl optionally substituted with one or more fluoro, or
(ii) optionally substituted benzyl. In one embodiment, R2 is
(C1-C4)alkyl or benzyl.

[0165] In specific embodiments, R2 is methyl. In specific
embodiments, R2 is trifluoromethyl. In specific embodiments, R2
is methyl or trifluoromethyl.

[0166] In one embodiment, R3 is hydrogen or (C1-C8)alkyl
optionally substituted with one or more optionally substituted aryl. In
one embodiment, R3 is hydrogen or (C1-C6)alkyl optionally
substituted with one or more optionally substituted aryl. In one
embodiment, R3 is hydrogen or (C1-C4)alkyl optionally
substituted with one or more optionally substituted aryl. In one
embodiment, R3 is hydrogen or (C1-C8)alkyl optionally
substituted with one or more optionally substituted heteroaryl. In one
embodiment, R3 is hydrogen or (C1-C6)alkyl optionally
substituted with one or more optionally substituted heteroaryl. In one
embodiment, R3 is hydrogen or (C1-C4)alkyl optionally
substituted with one or more optionally substituted heteroaryl. In one
embodiment, R3 is hydrogen or (C1-C8)alkyl optionally
substituted with one or more optionally substituted heterocyclyl. In one
embodiment, R3 is hydrogen or (C1-C6)alkyl optionally
substituted with one or more optionally substituted heterocyclyl. In one
embodiment, R3 is hydrogen or (C1-C4)alkyl optionally
substituted with one or more optionally substituted heterocyclyl. In one
embodiment, R3 is hydrogen or (C1-C8)alkyl optionally
substituted with one or more halogen. In one embodiment, R3 is
hydrogen or (C1-C6)alkyl optionally substituted with one or
more halogen. In one embodiment, R3 is hydrogen or
(C1-C4)alkyl optionally substituted with one or more halogen.
In one embodiment, the alkyl is optionally substituted with one or more
fluoro. In one embodiment, R3 is hydrogen, (C1-C8)alkyl
optionally substituted with one or more halogen, or
(C3-C8)cycloalkyl optionally substituted with one or more
halogen. In one embodiment, R3 is hydrogen, (C1-C6)alkyl
optionally substituted with one or more halogen, or
(C3-C6)cycloalkyl optionally substituted with one or more
halogen. In one embodiment, R3 is hydrogen, (C1-C4)alkyl
optionally substituted with one or more halogen, or
(C3-C4)cycloalkyl optionally substituted with one or more
halogen. In one embodiment, the alkyl or cycloalkyl is optionally
substituted with one or more fluoro. In one embodiment, R3 is
hydrogen, CH3, or CF3. In one embodiment, R3 is hydrogen
or (C1-C4)alkyl optionally substituted with one or more fluoro
or optionally substituted with phenyl. In one embodiment, R3 is
hydrogen, (C1-C4)alkyl optionally substituted with one or more
fluoro, or optionally substituted benzyl. In one embodiment, R3 is
hydrogen, (C1-C4)alkyl, or benzyl.

[0167] In specific embodiments, R3 is hydrogen.

[0168] In one embodiment, R4 is phenyl optionally substituted with
one or more halogen or CF3. In one embodiment, R4 is phenyl
substituted with one or more halogen or CF3. In one embodiment,
R4 is phenyl independently substituted at the 3- and 5-position with
halogen or CF3.

[0169] In one embodiment, R4 is phenyl optionally substituted with
one or more chloro or CF3. In one embodiment, R4 is phenyl
optionally substituted with one or more fluoro, chloro, or CF3. In
one embodiment, R4 is phenyl substituted with one or more chloro or
CF3. In one embodiment, R4 is phenyl substituted with one or
more fluoro, chloro, or CF3. In one embodiment, R4 is phenyl
independently substituted at the 3- and 5-position with chloro or
CF3. In one embodiment, R4 is phenyl independently substituted
at the 3- and 5-position with fluoro, chloro, or CF3.

[0170] In specific embodiments, R4 is:

##STR00011##

[0171] In specific embodiments, R4 is:

##STR00012##

[0172] In specific embodiments, R4 is:

##STR00013##

wherein R9 is hydrogen, chloro or CF3, R10 is hydrogen,
fluoro, chloro, or CF3, and R11 is hydrogen, fluoro, chloro,
CF3, or (C1-C4)alkyl. In one embodiment, R9 is
hydrogen, chloro or CF3, R10 is fluoro, chloro, or CF3,
and R11 is hydrogen, fluoro, chloro, CF3, or
(C1-C4)alkyl. In one embodiment, R9 is chloro or CF3,
R10 is fluoro, chloro, or CF3, and R11 is hydrogen,
fluoro, chloro, CF3, or (C1-C4)alkyl.

[0173] In specific embodiments, R4 is:

##STR00014##

[0174] In one embodiment, R4 is (5 to 6 membered)heteroaryl
optionally substituted with one or more halogen or CF3. In one
embodiment, R4 is (5 to 6 membered) heteroaryl substituted with one
or more halogen or CF3. In one embodiment, R4 is (5 to 6
membered)heteroaryl independently substituted at the 3- and 5-position
with halogen or CF3.

[0175] In one embodiment, R4 is (5 to 6 membered)heteroaryl
optionally substituted with one or more chloro or CF3. In one
embodiment, R4 is (5 to 6 membered)heteroaryl substituted with one
or more chloro or CF3. In one embodiment, R4 is (5 to 6
membered)heteroaryl independently substituted at the 3- and 5-position
with chloro or CF3.

[0176] In specific embodiments, R4 is:

##STR00015##

[0177] In one embodiment, R7 and R8 are each independently
fluoro, chloro, or

trifluoromethyl.

[0178] In one embodiment, each occurrence of X is CH.

[0179] In one embodiment, R9 and R10 are each independently
fluoro, chloro, or trifluoromethyl.

[0180] In one embodiment, R11 is H.

[0181] In one embodiment, R12 is fluoro, chloro, bromo, cyano,
hydroxyl, methyl, or methoxyl. In one embodiment, R12 is fluoro,
bromo, cyano, hydroxyl, methyl, or methoxyl. In one embodiment, R12
is fluoro, chloro, bromo, hydroxyl, methyl, or methoxyl. In one
embodiment, R12 is fluoro, bromo, hydroxyl, methyl, or methoxyl.

R1 is phenyl, 4-fluorophenyl, 4-chlorophenyl, or 4-bromophenyl; and
R2 is (C1-C4)alkyl optionally substituted with one or more
fluoro. In one embodiment, R1 is phenyl, 4-fluorophenyl,
4-chlorophenyl, 4-bromophenyl, or 4-methoxylphenyl; and R2 is
(C1-C4)alkyl optionally substituted with one or more fluoro. In
some embodiments, R1 is phenyl optionally substituted with one or
more fluoro and bromo, and R2 is (C1-C4)alkyl optionally
substituted with one or more fluoro. In some embodiments, R1 is
phenyl optionally substituted with one or more fluoro, bromo, or
methoxyl, and R2 is (C1-C4)alkyl optionally substituted
with one or more fluoro. In some embodiments, R1 is phenyl, and
R2 is (C1-C4)alkyl optionally substituted with one or more
fluoro.

R1 is phenyl, 4-fluorophenyl, 4-chlorophenyl, or 4-bromophenyl; and
R2 is (C1-C4)alkyl optionally substituted with one or more
fluoro. In one embodiment, R1 is phenyl, 4-fluorophenyl,
4-chlorophenyl, 4-bromophenyl, or 4-methoxylphenyl; and R2 is
(C1-C4)alkyl optionally substituted with one or more fluoro. In
some embodiments, R1 is phenyl optionally substituted with one or
more fluoro and bromo, and R2 is (C1-C4)alkyl optionally
substituted with one or more fluoro. In some embodiments, R1 is
phenyl optionally substituted with one or more fluoro, bromo, or
methoxyl, and R2 is (C1-C4)alkyl optionally substituted
with one or more fluoro. In some embodiments, R1 is phenyl, and
R2 is (C1-C4)alkyl optionally substituted with one or more
fluoro.

[0187] In one embodiment, specific examples of the compound of formula
(I), (III), (IV), or (V) include, but are not limited to, the following:

##STR00020## ##STR00021##

[0188] In one embodiment, when R4 is 3,5-di(trifluoromethyl)-phenyl,
R1 is not dichlorophenyl. In one embodiment, when R4 is
3,5-di(trifluoromethyl)-phenyl, R1 is not dihalophenyl. In one
embodiment, when R4 is 3,5-di(trifluoromethyl)-phenyl, R1 is
not phenyl optionally substituted with one or more chloro. In one
embodiment, when R4 is 3,5-di(trifluoromethyl)-phenyl, R1 is
not phenyl optionally substituted with one or more halogen.

[0189] It should be noted that if there is a discrepancy between a
depicted structure and a name given that structure, the depicted
structure is to be accorded more weight. In addition, if the
stereochemistry of a structure or a portion of a structure is not
indicated with, for example, bold or dashed lines, the structure or
portion of the structure is to be interpreted as encompassing all
stereoisomers of it. Where the compound provided herein contains an
alkenyl or alkenylene group, the compound may exist as one or mixture of
geometric cis/trans (or Z/E) isomers. Where structural isomers are
inter-convertible, the compound may exist as a single tautomer or a
mixture of tautomers. This can take the form of proton tautomerism in the
compound that contains, for example, an imino, keto, or oxime group; or
so-called valence tautomerism in the compound that contain an aromatic
moiety. It follows that a single compound may exhibit more than one type
of isomerism.

[0190] The compounds provided herein may be enantiomerically pure, such as
a single enantiomer or a single diastereomer, or be stereoisomeric
mixtures, such as a mixture of enantiomers, e.g., a racemic mixture of
two enantiomers; or a mixture of two or more diastereomers. In some
instances, for compounds that undergo epimerization in vivo, one of skill
in the art will recognize that administration of a compound in its (R)
form is equivalent to administration of the compound in its (S) form.
Conventional techniques for the preparation/isolation of individual
enantiomers include synthesis from a suitable optically pure precursor,
asymmetric synthesis from achiral starting materials, or resolution of an
enantiomeric mixture, for example, by chiral chromatography,
recrystallization, resolution, diastereomeric salt formation, or
derivatization into diastereomeric adducts followed by separation.

[0191] When the compound provided herein contains an acidic or basic
moiety, it may also be provided as a pharmaceutically acceptable salt
(See, e.g., Berge et al., J. Pharm. Sci. 1977, 66, 1-19; and Handbook of
Pharmaceutical Salts, Properties, and Use, Stahl and Wermuth, ed.;
Wiley-VCH and VHCA, Zurich, 2002).

[0194] In certain embodiments, the compounds provided herein are
pharmacologically acceptable salts of the compounds with one or more of
hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic,
salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic,
and isoethonic acids; or with one or more of potassium carbonate, sodium
or potassium hydroxide, ammonia, triethylamine, and triethanolamine.

[0196] Schemes below provide exemplary synthetic methods for the
preparation of the compounds provided herein. One of ordinary skill in
the art will understand that similar methods may be employed to prepare
the compounds provided herein. In other words, one of ordinary skill in
the art will recognize that suitable adjustments to reagents, protecting
groups, reaction conditions, and reaction sequences may be employed to
prepare a desired embodiment. The reaction may be scaled upwards or
downwards to suit the amount of material to be prepared. In one
embodiment, the compounds provided herein may be prepared by the
procedures and techniques similar to those disclosed in the Examples. In
one embodiment, the compounds provided herein may be prepared by
procedures and techniques known in the art for coupling sulfonyl
chlorides or acid chlorides with amines. In one embodiment, the sulfonyl
chlorides or acid chlorides are prepared by procedures and techniques
known in the art. In one embodiment, the compounds provided herein may be
prepared by procedures and techniques known in the art for coupling acid
chlorides with amines. In one embodiment, the acid chlorides are prepared
by procedures and techniques known in the art, for example, from the
corresponding carboxylic acid. In one embodiment, the compounds provided
herein may be prepared by procedures and techniques known in the art for
coupling carboxylic acid with amines, e.g., in the presence of a suitable
coupling reagent.

[0197] In one embodiment, the starting material used to prepared the
compounds provided herein may be obtained from a commercial source. In
one embodiment, the starting material used to prepared the compounds
provided herein may be prepared following the procedures or conditions
known in the art.

[0198] In one embodiment, the compounds provided herein may be prepared
following Scheme 1 and 2. In one embodiment, the compounds are prepared
by adding an excess of the respective sulfonyl chloride or acid chloride
to a solution of a suitable amine, and a base, such as, e.g.,
N,N-diisopropylethylamine, in a solvent, such as, e.g., dichloromethane.
In one embodiment, after the reaction is stirred at room temperature
until the reaction is complete, as monitored by, e.g., thin layer
chromatography. In one embodiment, the reaction undergoes an aqueous
workup washing with dilute HCl, followed by dilute aqueous NaHCO3
solution and brine. In one embodiment, after the aqueous workup the
reaction mixture is dried over MgSO4 and concentrated. In one
embodiment, the compound may be further purified by column chromatography
or by passing through a silica gel plug using an eluent, such as ethyl
acetate/hexanes. In one embodiment, the compound is analyzed by LCMS. In
one embodiment, the compound is analyzed by 1H NMR.

[0199] In one embodiment, a compound of formula (II) may be prepared
following Scheme 1, wherein the intermediates II-A and II-B may be
obtained from a commercial source or prepared following procedures known
in the art. R1, R2, R3, and R4 are as defined herein
elsewhere. In one embodiment, the base used in the reaction of Scheme 1
is triethylamine or diisopropylethylamine. In one embodiment, the
reaction of Scheme 1 is carried out in an aprotic solvent. In one
embodiment, the reaction of Scheme 1 is carried out in dichloromethane.

[0200] In one embodiment, the compounds provided herein may be made by the
procedures and techniques disclosed in the Examples, as well as known
organic synthesis techniques for coupling sulfonyl chlorides and amines.

##STR00022##

[0201] In one embodiment, a compound of formula (III) may be prepared
following Scheme 2, wherein the intermediates III-A and III-B may be
obtained from a commercial source or prepared following procedures known
in the art. In one embodiment, intermediate III-A is an acid, an acid
anhydride, or an acid chloride. In one embodiment, Z is chloro. In one
embodiment, Z is OH. In one embodiment, Z is --O-acyl, wherein III-A is
an acid anhydride. R1, R2, R3, R7, R8, and X are
as defined herein elsewhere. In one embodiment, the reaction of Scheme 2
is carried out in an aprotic solvent. In one embodiment, the reaction of
Scheme 2 is carried out at elevated temperature. In one embodiment, the
reaction of Scheme 2 is carried out at room temperature. In one
embodiment, the reaction of Scheme 2 is carried out in the presence of
one or more amide coupling reagents known in the art, such as, e.g., HOBt
or EDCl. In one embodiment, the reaction of Scheme 2 is carried out in
the presence of a catalyst known in the art to facilitate the amide
coupling, such as, e.g., DMAP. In one embodiment, the reaction of Scheme
2 is carried out in the presence of a base, such as, e.g., triethylamine
or diisopropylethylamine, in a solvent, such as, dichloromethane.

##STR00023##

##STR00024##

[0202] In one embodiment, a compound of formula (IV) may be prepared
following Scheme 3, wherein the intermediates IV-A and IV-B may be
obtained from a commercial source or prepared following procedures known
in the art. In one embodiment, intermediate IV-A is an acid, an acid
anhydride, or an acid chloride. In one embodiment, Z is chloro. In one
embodiment, Z is OH. In one embodiment, Z is --O-acyl, wherein IV-A is an
acid anhydride. R1, R2, R3, R9, R10, and
R11 are as defined herein elsewhere. In one embodiment, the reaction
of Scheme 3 is carried out in an aprotic solvent. In one embodiment, the
reaction of Scheme 3 is carried out at elevated temperature. In one
embodiment, the reaction of Scheme 3 is carried out at room temperature.
In one embodiment, the reaction of Scheme 3 is carried out in the
presence of one or more amide coupling reagents known in the art, such
as, e.g., HOBt or EDCl. In one embodiment, the reaction of Scheme 3 is
carried out in the presence of a catalyst known in the art to facilitate
the amide coupling, such as, e.g., DMAP. In one embodiment, the reaction
of Scheme 3 is carried out in the presence of a base, such as, e.g.,
triethylamine or diisopropylethylamine.

[0203] In one embodiment, the compounds provided herein may be made by the
procedures and techniques disclosed in the Examples, as well as known
organic synthesis techniques for coupling acid chlorides and amines.

[0204] In one embodiment, R3 is hydrogen in Scheme 1, Scheme 2, and
Scheme 3.

##STR00025##

[0205] In one embodiment, a compound of formula (II), (III), or (IV) may
be prepared following Scheme 4, wherein R1, R2, R4,
R7, R8, R9, R10, R11, and X are as defined
herein elsewhere, R3 is an optionally substituted alkyl, and Y is
chloro, bromo, or iodo. In one embodiment, intermediates II-C, III-C, and
IV-C may be prepared following procedures and conditions provided in
Schemes 1-3. In one embodiment, the alkylation reaction may be carried
out using an alkylating reagent, such as iodoalkane or bromoalkane (e.g.,
iodomethane or benzyl bromide), and a base, such as potassium carbonate,
in a solvent, such as dimethylformamide, at ambient or elevated
temperatures. In one embodiment, the reaction mixture is stirred until
the reaction is complete, as monitored by thin layer chromatography. In
one embodiment, the reaction mixture is concentrated, taken up in
dichloromethane, and the dichloromethane solution undergoes an aqueous
workup, washing with dilute HCl, followed by dilute NaHCO3, and
brine. In one embodiment, after the aqueous workup, the reaction mixture
is dried over MgSO4 and concentrated. In one embodiment, the
compound may be purified by column chromatography or by passing through a
silica gel plug using an eluent, such as ethyl acetate/hexanes. In one
embodiment, the compound is analyzed by LCMS. In one embodiment, the
compound is analyzed by 1H NMR.

D. Pharmaceutical Compositions

[0206] In one embodiment, provided herein is a pharmaceutical composition
comprising a compound of formula (I) as defined herein elsewhere, or an
enantiomer, a mixture of enantiomers or a mixture of diastereomers
thereof, or a pharmaceutically acceptable salt, solvate, hydrate or
prodrug thereof, and at least one pharmaceutically acceptable excipient,
adjuvant, carrier, buffer, or stabiliser.

[0207] In one embodiment, the pharmaceutically acceptable excipient,
adjuvant, carrier, buffer, or stabiliser is non-toxic and does not
interfere with the efficacy of the active ingredient. The precise nature
of the carrier or other material will depend on the route of
administration, which may be oral or by injection, such as cutaneous,
subcutaneous, or intravenous injection.

[0208] In one embodiment, the pharmaceutical compositions are provided in
a dosage form for oral administration, which comprise a compound provided
herein, e.g., a compound of formula (I), or an enantiomer, a mixture of
enantiomers or a mixture of diastereomers thereof, or a pharmaceutically
acceptable salt, solvate, hydrate or prodrug thereof, and one or more
pharmaceutically acceptable excipients or carriers. The pharmaceutical
compositions provided herein that are formulated for oral administration
may be in tablet, capsule, powder, or liquid form. A tablet may comprise
a solid carrier or an adjuvant. Liquid pharmaceutical compositions
generally comprise a liquid carrier such as water, petroleum, animal or
vegetable oils, or mineral oil or synthetic oil. Physiological saline
solution, dextrose or other saccharide solution, or glycols such as
ethylene glycol, propylene glycol, or polyethylene glycol may be
included. A capsule may comprise a solid carrier such as gelatin.

[0209] In another embodiment, the pharmaceutical compositions are provided
in a dosage form for parenteral administration, and one or more
pharmaceutically acceptable excipients or carriers. Where pharmaceutical
compositions may be formulated for intravenous, cutaneous or subcutaneous
injection, the active ingredient will be in the form of a parenterally
acceptable aqueous solution, which is pyrogen-free and has a suitable pH,
isotonicity, and stability. Those of relevant skill in the art are well
able to prepare suitable solutions using, for example, isotonic vehicles,
such as Sodium Chloride injection, Ringer's injection, or Lactated
Ringer's injection. Preservatives, stabilisers, buffers, antioxidants,
and/or other additives may be included as required.

[0210] In yet another embodiment, the pharmaceutical compositions are
provided in a dosage form for topical administration, which comprise a
compound provided herein, and one or more pharmaceutically acceptable
excipients or carriers.

[0211] In one embodiment, the pharmaceutical compositions can also be
formulated as modified release dosage forms, including delayed-,
extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated-
and fast-, targeted-, programmed-release, and gastric retention dosage
forms. These dosage forms can be prepared according to conventional
methods and techniques known to those skilled in the art (see, e.g.,
Remington: The Science and Practice of Pharmacy, supra; Modified-Release
Drug Delivery Technology, 2nd Ed., Rathbone et al., eds., Marcel Dekker,
Inc.: New York, N.Y., 2008).

[0212] In one embodiment, the pharmaceutical compositions provided herein
can be provided in a unit-dosage form or multiple-dosage form. A
unit-dosage form, as used herein, refers to physically discrete a unit
suitable for administration to a human and animal subject, and packaged
individually as is known in the art. Each unit-dose contains a
predetermined quantity of an active ingredient(s) sufficient to produce
the desired therapeutic effect, in association with the required
pharmaceutical carriers or excipients. Examples of a unit-dosage form
include an ampoule, syringe, and individually packaged tablet and
capsule. A unit-dosage form may be administered in fractions or multiples
thereof. A multiple-dosage form is a plurality of identical unit-dosage
forms packaged in a single container to be administered in segregated
unit-dosage form. Examples of a multiple-dosage form include a vial,
bottle of tablets or capsules, or bottle of pints or gallons.

[0213] In one embodiment, the pharmaceutical compositions provided herein
can be administered at once, or multiple times at intervals of time. It
is understood that the precise dosage and duration of treatment may vary
with the age, weight, and condition of the patient being treated, and may
be determined empirically using known testing protocols or by
extrapolation from in vivo or in vitro test or diagnostic data. It is
further understood that for any particular individual, specific dosage
regimens should be adjusted over time according to the individual need
and the professional judgment of the person administering or supervising
the administration of the formulations.

[0214] In another embodiment, the pharmaceutical compositions provided
herein further comprise one or more chemotherapeutic agents as defined
herein.

[0215] In yet another embodiment, provided herein is the use of a compound
of formula (I), or an enantiomer, a mixture of enantiomers or a mixture
of diastereomers thereof, or a pharmaceutically acceptable salt, solvate,
hydrate or prodrug thereof, in the manufacture of a medicament for the
treatment of one or more disorders disclosed herein. In certain
embodiments, the medicament is in tablet, capsule, powder, or liquid
form. In certain embodiments, the medicament is formulated as described
herein.

[0219] In one embodiment, suitable diluents include, but are not limited
to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose,
inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch, and
powdered sugar. Certain diluents, such as mannitol, lactose, sorbitol,
sucrose, and inositol, when present in sufficient quantity, can impart
properties to some compressed tablets that permit disintegration in the
mouth by chewing. Such compressed tablets can be used as chewable
tablets. The amount of a diluent in the pharmaceutical compositions
provided herein varies upon the type of formulation, and is readily
discernible to those of ordinary skill in the art.

[0220] In one embodiment, suitable disintegrants include, but are not
limited to, agar; bentonite; celluloses, such as methylcellulose and
carboxymethylcellulose; wood products; natural sponge; cation-exchange
resins; alginic acid; gums, such as guar gum and Veegum HV; citrus pulp;
cross-linked celluloses, such as croscarmellose; cross-linked polymers,
such as crospovidone; cross-linked starches; calcium carbonate;
microcrystalline cellulose, such as sodium starch glycolate; polacrilin
potassium; starches, such as corn starch, potato starch, tapioca starch,
and pre-gelatinized starch; clays; aligns; and mixtures thereof. The
amount of a disintegrant in the pharmaceutical compositions provided
herein varies upon the type of formulation, and is readily discernible to
those of ordinary skill in the art. The amount of a disintegrant in the
pharmaceutical compositions provided herein varies upon the type of
formulation, and is readily discernible to those of ordinary skill in the
art. The pharmaceutical compositions provided herein may contain from
about 0.5 to about 15% or from about 1 to about 5% by weight of a
disintegrant.

[0222] In one embodiment, suitable glidants include, but are not limited
to, colloidal silicon dioxide, CAB-O-SIL® (Cabot Co. of Boston,
Mass.), and asbestos-free talc. Suitable coloring agents include, but are
not limited to, any of the approved, certified, water soluble FD&C dyes,
and water insoluble FD&C dyes suspended on alumina hydrate, and color
lakes and mixtures thereof. A color lake is the combination by adsorption
of a water-soluble dye to a hydrous oxide of a heavy metal, resulting in
an insoluble form of the dye. Suitable flavoring agents include, but are
not limited to, natural flavors extracted from plants, such as fruits,
and synthetic blends of compounds which produce a pleasant taste
sensation, such as peppermint and methyl salicylate. Suitable sweetening
agents include, but are not limited to, sucrose, lactose, mannitol,
syrups, glycerin, and artificial sweeteners, such as saccharin and
aspartame. Suitable emulsifying agents include, but are not limited to,
gelatin, acacia, tragacanth, bentonite, and surfactants, such as
polyoxyethylene sorbitan monooleate (TWEEN® 20), polyoxyethylene
sorbitan monooleate 80 (TWEEN® 80), and triethanolamine oleate.
Suitable suspending and dispersing agents include, but are not limited
to, sodium carboxymethylcellulose, pectin, tragacanth, Veegum, acacia,
sodium carbomethylcellulose, hydroxypropyl methylcellulose, and
polyvinylpyrrolidone. Suitable preservatives include, but are not limited
to, glycerin, methyl and propylparaben, benzoic add, sodium benzoate and
alcohol. Suitable wetting agents include, but are not limited to,
propylene glycol monostearate, sorbitan monooleate, diethylene glycol
monolaurate, and polyoxyethylene lauryl ether. Suitable solvents include,
but are not limited to, glycerin, sorbitol, ethyl alcohol, and syrup.
Suitable non-aqueous liquids utilized in emulsions include, but are not
limited to, mineral oil and cottonseed oil. Suitable organic acids
include, but are not limited to, citric and tartaric acid. Suitable
sources of carbon dioxide include, but are not limited to, sodium
bicarbonate and sodium carbonate.

[0223] It should be understood that many carriers and excipients may serve
several functions, even within the same formulation.

[0224] In one embodiment, the pharmaceutical compositions provided herein
for oral administration can be provided as compressed tablets, tablet
triturates, chewable lozenges, rapidly dissolving tablets, multiple
compressed tablets, or enteric-coating tablets, sugar-coated, or
film-coated tablets. Enteric-coated tablets are compressed tablets coated
with substances that resist the action of stomach acid but dissolve or
disintegrate in the intestine, thus protecting the active ingredients
from the acidic environment of the stomach. Enteric-coatings include, but
are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac,
ammoniated shellac, and cellulose acetate phthalates. Sugar-coated
tablets are compressed tablets surrounded by a sugar coating, which may
be beneficial in covering up objectionable tastes or odors and in
protecting the tablets from oxidation. Film-coated tablets are compressed
tablets that are covered with a thin layer or film of a water-soluble
material. Film coatings include, but are not limited to,
hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol
4000, and cellulose acetate phthalate. Film coating imparts the same
general characteristics as sugar coating. Multiple compressed tablets are
compressed tablets made by more than one compression cycle, including
layered tablets, and press-coated or dry-coated tablets.

[0225] In one embodiment, the tablet dosage forms can be prepared from the
active ingredient in powdered, crystalline, or granular forms, alone or
in combination with one or more carriers or excipients described herein,
including binders, disintegrants, controlled-release polymers,
lubricants, diluents, and/or colorants. Flavoring and sweetening agents
are especially useful in the formation of chewable tablets and lozenges.

[0226] In one embodiment, the pharmaceutical compositions provided herein
for oral administration can be provided as soft or hard capsules, which
can be made from gelatin, methylcellulose, starch, or calcium alginate.
The hard gelatin capsule, also known as the dry-filled capsule (DFC),
consists of two sections, one slipping over the other, thus completely
enclosing the active ingredient. The soft elastic capsule (SEC) is a
soft, globular shell, such as a gelatin shell, which is plasticized by
the addition of glycerin, sorbitol, or a similar polyol. The soft gelatin
shells may contain a preservative to prevent the growth of
microorganisms. Suitable preservatives are those as described herein,
including methyl- and propyl-parabens, and sorbic acid. The liquid,
semisolid, and solid dosage forms provided herein may be encapsulated in
a capsule. Suitable liquid and semisolid dosage forms include solutions
and suspensions in propylene carbonate, vegetable oils, or triglycerides.
Capsules containing such solutions can be prepared as described in U.S.
Pat. Nos. 4,328,245; 4,409,239; and 4,410,545. The capsules may also be
coated as known by those of skill in the art in order to modify or
sustain dissolution of the active ingredient.

[0227] In one embodiment, the pharmaceutical compositions provided herein
for oral administration can be provided in liquid and semisolid dosage
forms, including emulsions, solutions, suspensions, elixirs, and syrups.
An emulsion is a two-phase system, in which one liquid is dispersed in
the form of small globules throughout another liquid, which can be
oil-in-water or water-in-oil. Emulsions may include a pharmaceutically
acceptable non-aqueous liquid or solvent, emulsifying agent, and
preservative. Suspensions may include a pharmaceutically acceptable
suspending agent and preservative. Aqueous alcoholic solutions may
include a pharmaceutically acceptable acetal, such as a di(lower
alkyl)acetal of a lower alkyl aldehyde, e.g., acetaldehyde diethyl
acetal; and a water-miscible solvent having one or more hydroxyl groups,
such as propylene glycol and ethanol. Elixirs are clear, sweetened, and
hydroalcoholic solutions. Syrups are concentrated aqueous solutions of a
sugar, for example, sucrose, and may also contain a preservative. For a
liquid dosage form, for example, a solution in a polyethylene glycol may
be diluted with a sufficient quantity of a pharmaceutically acceptable
liquid carrier, e.g., water, to be measured conveniently for
administration.

[0229] In one embodiment, the pharmaceutical compositions provided herein
for oral administration can be also provided in the forms of liposomes,
micelles, microspheres, or nanosystems. Micellar dosage forms can be
prepared as described in U.S. Pat. No. 6,350,458.

[0230] In one embodiment, the pharmaceutical compositions provided herein
for oral administration can be provided as non-effervescent or
effervescent, granules and powders, to be reconstituted into a liquid
dosage form. Pharmaceutically acceptable carriers and excipients used in
the non-effervescent granules or powders may include diluents,
sweeteners, and wetting agents. Pharmaceutically acceptable carriers and
excipients used in the effervescent granules or powders may include
organic acids and a source of carbon dioxide.

[0231] In one embodiment, coloring and flavoring agents can be used in all
of the above dosage forms.

[0232] In one embodiment, the pharmaceutical compositions provided herein
for oral administration can be formulated as immediate or modified
release dosage forms, including delayed-, sustained, pulsed-, controlled,
targeted-, and programmed-release forms.

[0233] 2. Parenteral Administration

[0234] In one embodiment, the pharmaceutical compositions provided herein
can be administered parenterally by injection, infusion, or implantation,
for local or systemic administration. Parenteral administration, as used
herein, include intravenous, intraarterial, intraperitoneal, intrathecal,
intraventricular, intraurethral, intrasternal, intracranial,
intramuscular, intrasynovial, intravesical, and subcutaneous
administration.

[0235] In one embodiment, the pharmaceutical compositions provided herein
for parenteral administration can be formulated in any dosage forms that
are suitable for parenteral administration, including solutions,
suspensions, emulsions, micelles, liposomes, microspheres, nanosystems,
and solid forms suitable for solutions or suspensions in liquid prior to
injection. Such dosage forms can be prepared according to conventional
methods known to those skilled in the art of pharmaceutical science (see,
e.g., Remington: The Science and Practice of Pharmacy, supra).

[0238] In one embodiment, suitable antimicrobial agents or preservatives
include, but are not limited to, phenols, cresols, mercurials, benzyl
alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoates, thimerosal,
benzalkonium chloride (e.g., benzethonium chloride), methyl- and
propyl-parabens, and sorbic acid. Suitable isotonic agents include, but
are not limited to, sodium chloride, glycerin, and dextrose. Suitable
buffering agents include, but are not limited to, phosphate and citrate.
Suitable antioxidants are those as described herein, including bisulfite
and sodium metabisulfite. Suitable local anesthetics include, but are not
limited to, procaine hydrochloride. Suitable suspending and dispersing
agents are those as described herein, including sodium
carboxymethylcelluose, hydroxypropyl methylcellulose, and
polyvinylpyrrolidone. Suitable emulsifying agents are those described
herein, including polyoxyethylene sorbitan monolaurate, polyoxyethylene
sorbitan monooleate 80, and triethanolamine oleate. Suitable sequestering
or chelating agents include, but are not limited to EDTA. Suitable pH
adjusting agents include, but are not limited to, sodium hydroxide,
hydrochloric acid, citric acid, and lactic acid. Suitable complexing
agents include, but are not limited to, cyclodextrins, including
α-cyclodextrin, β-cyclodextrin,
hydroxypropyl-β-cyclodextrin, sulfobutylether-β-cyclodextrin,
and sulfobutylether 7-β-cyclodextrin (CAPTISOL®, CyDex, Lenexa,
Kans.).

[0239] In one embodiment, when the pharmaceutical compositions provided
herein are formulated for multiple dosage administration, the multiple
dosage parenteral formulations must contain an antimicrobial agent at
bacteriostatic or fungistatic concentrations. All parenteral formulations
must be sterile, as known and practiced in the art.

[0240] In one embodiment, the pharmaceutical compositions for parenteral
administration are provided as ready-to-use sterile solutions. In another
embodiment, the pharmaceutical compositions are provided as sterile dry
soluble products, including lyophilized powders and hypodermic tablets,
to be reconstituted with a vehicle prior to use. In yet another
embodiment, the pharmaceutical compositions are provided as ready-to-use
sterile suspensions. In yet another embodiment, the pharmaceutical
compositions are provided as sterile dry insoluble products to be
reconstituted with a vehicle prior to use. In still another embodiment,
the pharmaceutical compositions are provided as ready-to-use sterile
emulsions.

[0241] In one embodiment, the pharmaceutical compositions provided herein
for parenteral administration can be formulated as immediate or modified
release dosage forms, including delayed-, sustained, pulsed-, controlled,
targeted-, and programmed-release forms.

[0242] In one embodiment, the pharmaceutical compositions provided herein
for parenteral administration can be formulated as a suspension, solid,
semi-solid, or thixotropic liquid, for administration as an implanted
depot. In one embodiment, the pharmaceutical compositions provided herein
are dispersed in a solid inner matrix, which is surrounded by an outer
polymeric membrane that is insoluble in body fluids but allows the active
ingredient in the pharmaceutical compositions diffuse through.

[0246] In one embodiment, the pharmaceutical compositions provided herein
can be administered topically to the skin, orifices, or mucosa. The
topical administration, as used herein, includes (intra)dermal,
conjunctival, intracorneal, intraocular, ophthalmic, auricular,
transdermal, nasal, vaginal, urethral, respiratory, and rectal
administration.

[0249] In one embodiment, the pharmaceutical compositions can also be
administered topically by electroporation, iontophoresis, phonophoresis,
sonophoresis, or microneedle or needle-free injection, such as
POWDERJECT® (Chiron Corp., Emeryville, Calif.), and BIOJECT®
(Bioject Medical Technologies Inc., Tualatin, Oreg.).

[0250] In one embodiment, the pharmaceutical compositions provided herein
can be provided in the forms of ointments, creams, and gels. Suitable
ointment vehicles include oleaginous or hydrocarbon vehicles, including
lard, benzoinated lard, olive oil, cottonseed oil, and other oils, white
petrolatum; emulsifiable or absorption vehicles, such as hydrophilic
petrolatum, hydroxystearin sulfate, and anhydrous lanolin;
water-removable vehicles, such as hydrophilic ointment; water-soluble
ointment vehicles, including polyethylene glycols of varying molecular
weight; emulsion vehicles, either water-in-oil (W/O) emulsions or
oil-in-water (O/W) emulsions, including cetyl alcohol, glyceryl
monostearate, lanolin, and stearic acid (see, e.g., Remington: The
Science and Practice of Pharmacy, supra). These vehicles are emollient
but generally require addition of antioxidants and preservatives.

[0251] In one embodiment, suitable cream base can be oil-in-water or
water-in-oil. Suitable cream vehicles may be water-washable, and contain
an oil phase, an emulsifier, and an aqueous phase. The oil phase is also
called the "internal" phase, which is generally comprised of petrolatum
and a fatty alcohol such as cetyl or stearyl alcohol. The aqueous phase
usually, although not necessarily, exceeds the oil phase in volume, and
generally contains a humectant. The emulsifier in a cream formulation may
be a nonionic, anionic, cationic, or amphoteric surfactant.

[0252] In one embodiment, gels are semisolid, suspension-type systems.
Single-phase gels contain organic macromolecules distributed
substantially uniformly throughout the liquid carrier. Suitable gelling
agents include, but are not limited to, crosslinked acrylic acid
polymers, such as carbomers, carboxypolyalkylenes, and CARBOPOL®;
hydrophilic polymers, such as polyethylene oxides,
polyoxyethylene-polyoxypropylene copolymers, and polyvinylalcohol;
cellulosic polymers, such as hydroxypropyl cellulose, hydroxyethyl
cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose
phthalate, and methylcellulose; gums, such as tragacanth and xanthan gum;
sodium alginate; and gelatin. In order to prepare a uniform gel,
dispersing agents such as alcohol or glycerin can be added, or the
gelling agent can be dispersed by trituration, mechanical mixing, and/or
stirring.

[0253] In one embodiment, the pharmaceutical compositions provided herein
can be administered rectally, urethrally, vaginally, or perivaginally in
the forms of suppositories, pessaries, bougies, poultices or cataplasm,
pastes, powders, dressings, creams, plasters, contraceptives, ointments,
solutions, emulsions, suspensions, tampons, gels, foams, sprays, or
enemas. These dosage forms can be manufactured using conventional
processes as described in Remington: The Science and Practice of
Pharmacy, supra.

[0254] In one embodiment, rectal, urethral, and vaginal suppositories are
solid bodies for insertion into body orifices, which are solid at
ordinary temperatures but melt or soften at body temperature to release
the active ingredient(s) inside the orifices. Pharmaceutically acceptable
carriers utilized in rectal and vaginal suppositories include bases or
vehicles, such as stiffening agents, which produce a melting point in the
proximity of body temperature, when formulated with the pharmaceutical
compositions provided herein; and antioxidants as described herein,
including bisulfite and sodium metabisulfite. Suitable vehicles include,
but are not limited to, cocoa butter (theobroma oil), glycerin-gelatin,
carbowax (polyoxyethylene glycol), spermaceti, paraffin, white and yellow
wax, and appropriate mixtures of mono-, di- and triglycerides of fatty
acids, and hydrogels, such as polyvinyl alcohol, hydroxyethyl
methacrylate, and polyacrylic acid. Combinations of the various vehicles
can also be used. Rectal and vaginal suppositories may be prepared by
compressing or molding. The typical weight of a rectal and vaginal
suppository is about 2 to about 3 g.

[0255] In one embodiment, the pharmaceutical compositions provided herein
can be administered ophthalmically in the forms of solutions,
suspensions, ointments, emulsions, gel-forming solutions, powders for
solutions, gels, ocular inserts, and implants.

[0256] In one embodiment, the pharmaceutical compositions provided herein
can be administered intranasally or by inhalation to the respiratory
tract. The pharmaceutical compositions can be provided in the form of an
aerosol or solution for delivery using a pressurized container, pump,
spray, atomizer, such as an atomizer using electrohydrodynamics to
produce a fine mist, or nebulizer, alone or in combination with a
suitable propellant, such as 1,1,1,2-tetrafluoroethane or
1,1,1,2,3,3,3-heptafluoropropane. The pharmaceutical compositions can
also be provided as a dry powder for insufflation, alone or in
combination with an inert carrier such as lactose or phospholipids; and
nasal drops. For intranasal use, the powder can comprise a bioadhesive
agent, including chitosan or cyclodextrin.

[0257] In one embodiment, solutions or suspensions for use in a
pressurized container, pump, spray, atomizer, or nebulizer can be
formulated to contain ethanol, aqueous ethanol, or a suitable alternative
agent for dispersing, solubilizing, or extending release of the active
ingredient provided herein; a propellant as solvent; and/or a surfactant,
such as sorbitan trioleate, oleic acid, or an oligolactic acid.

[0258] In one embodiment, the pharmaceutical compositions provided herein
can be micronized to a size suitable for delivery by inhalation, such as
about 50 micrometers or less, or about 10 micrometers or less. Particles
of such sizes can be prepared using a comminuting method known to those
skilled in the art, such as spiral jet milling, fluid bed jet milling,
supercritical fluid processing to form nanoparticles, high pressure
homogenization, or spray drying.

[0259] In one embodiment, capsules, blisters, and cartridges for use in an
inhaler or insufflator can be formulated to contain a powder mix of the
pharmaceutical compositions provided herein; a suitable powder base, such
as lactose or starch; and a performance modifier, such as l-leucine,
mannitol, or magnesium stearate. The lactose may be anhydrous or in the
form of the monohydrate. Other suitable excipients or carriers include,
but are not limited to, dextran, glucose, maltose, sorbitol, xylitol,
fructose, sucrose, and trehalose. The pharmaceutical compositions
provided herein for inhaled/intranasal administration can further
comprise a suitable flavor, such as menthol and levomenthol; and/or
sweeteners, such as saccharin and saccharin sodium.

[0260] In one embodiment, the pharmaceutical compositions provided herein
for topical administration can be formulated to be immediate release or
modified release, including delayed-, sustained-, pulsed-, controlled-,
targeted, and programmed release.

[0261] 4. Modified Release

[0262] In one embodiment, the pharmaceutical compositions provided herein
can be formulated as a modified release dosage form. As used herein, the
term "modified release" refers to a dosage form in which the rate or
place of release of the active ingredient(s) is different from that of an
immediate dosage form when administered by the same route. Modified
release dosage forms include, but are not limited to, delayed-,
extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated-
and fast-, targeted-, programmed-release, and gastric retention dosage
forms. The pharmaceutical compositions in modified release dosage forms
can be prepared using a variety of modified release devices and methods
known to those skilled in the art, including, but not limited to, matrix
controlled release devices, osmotic controlled release devices,
multiparticulate controlled release devices, ion-exchange resins, enteric
coatings, multilayered coatings, microspheres, liposomes, and
combinations thereof. The release rate of the active ingredient(s) can
also be modified by varying the particle sizes and polymorphorism of the
active ingredient(s).

[0264] In one embodiment, the pharmaceutical compositions provided herein
in a modified release dosage form can be fabricated using a matrix
controlled release device known to those skilled in the art (see, e.g.,
Takada et al. in Encyclopedia of Controlled Drug Delivery, Vol. 2,
Mathiowitz Ed., Wiley, 1999).

[0265] In certain embodiments, the pharmaceutical compositions provided
herein in a modified release dosage form is formulated using an erodible
matrix device, which is water-swellable, erodible, or soluble polymers,
including, but not limited to, synthetic polymers, and naturally
occurring polymers and derivatives, such as polysaccharides and proteins.

[0268] In one embodiment, in a matrix controlled release system, the
desired release kinetics can be controlled, for example, via the polymer
type employed, the polymer viscosity, the particle sizes of the polymer
and/or the active ingredient(s), the ratio of the active ingredient(s)
versus the polymer, and other excipients or carriers in the compositions.

[0269] In one embodiment, the pharmaceutical compositions provided herein
in a modified release dosage form can be prepared by methods known to
those skilled in the art, including direct compression, dry or wet
granulation followed by compression, and melt-granulation followed by
compression.

(b) Osmotic Controlled Release Devices

[0270] In one embodiment, the pharmaceutical compositions provided herein
in a modified release dosage form can be fabricated using an osmotic
controlled release device, including, but not limited to, one-chamber
system, two-chamber system, asymmetric membrane technology (AMT), and
extruding core system (ECS). In general, such devices have at least two
components: (a) a core which contains an active ingredient; and (b) a
semipermeable membrane with at least one delivery port, which
encapsulates the core. The semipermeable membrane controls the influx of
water to the core from an aqueous environment of use so as to cause drug
release by extrusion through the delivery port(s).

[0273] In one embodiment, osmotic agents of different dissolution rates
can be employed to influence how rapidly the active ingredient(s) is
initially delivered from the dosage form. For example, amorphous sugars,
such as MANNOGEM® EZ (SPI Pharma, Lewes, D E) can be used to provide
faster delivery during the first couple of hours to promptly produce the
desired therapeutic effect, and gradually and continually release of the
remaining amount to maintain the desired level of therapeutic or
prophylactic effect over an extended period of time. In this case, the
active ingredient(s) is released at such a rate to replace the amount of
the active ingredient metabolized and excreted.

[0274] In one embodiment, the core can also include a wide variety of
other excipients and carriers as described herein to enhance the
performance of the dosage form or to promote stability or processing.

[0276] In one embodiment, semipermeable membrane can also be a hydrophobic
microporous membrane, wherein the pores are substantially filled with a
gas and are not wetted by the aqueous medium but are permeable to water
vapor, as disclosed in U.S. Pat. No. 5,798,119. Such hydrophobic but
water-vapor permeable membrane are typically composed of hydrophobic
polymers such as polyalkenes, polyethylene, polypropylene,
polytetrafluoroethylene, polyacrylic acid derivatives, polyethers,
polysulfones, polyethersulfones, polystyrenes, polyvinyl halides,
polyvinylidene fluoride, polyvinyl esters and ethers, natural waxes, and
synthetic waxes.

[0277] In one embodiment, the delivery port(s) on the semipermeable
membrane can be formed post-coating by mechanical or laser drilling.
Delivery port(s) can also be formed in situ by erosion of a plug of
water-soluble material or by rupture of a thinner portion of the membrane
over an indentation in the core. In addition, delivery ports can be
formed during coating process, as in the case of asymmetric membrane
coatings of the type disclosed in U.S. Pat. Nos. 5,612,059 and 5,698,220.

[0278] In one embodiment, the total amount of the active ingredient(s)
released and the release rate can substantially by modulated via the
thickness and porosity of the semipermeable membrane, the composition of
the core, and the number, size, and position of the delivery ports.

[0279] In one embodiment, the pharmaceutical compositions in an osmotic
controlled-release dosage form can further comprise additional
conventional excipients or carriers as described herein to promote
performance or processing of the formulation.

[0281] In certain embodiments, the pharmaceutical compositions provided
herein are formulated as AMT controlled-release dosage form, which
comprises an asymmetric osmotic membrane that coats a core comprising the
active ingredient(s) and other pharmaceutically acceptable excipients or
carriers. See, e.g., U.S. Pat. No. 5,612,059 and WO 2002/17918. The AMT
controlled-release dosage forms can be prepared according to conventional
methods and techniques known to those skilled in the art, including
direct compression, dry granulation, wet granulation, and a dip-coating
method.

[0282] In certain embodiments, the pharmaceutical compositions provided
herein are formulated as ESC controlled-release dosage form, which
comprises an osmotic membrane that coats a core comprising the active
ingredient(s), a hydroxylethyl cellulose, and other pharmaceutically
acceptable excipients or carriers.

(c) Multiparticulate Controlled Release Devices

[0283] In one embodiment, the pharmaceutical compositions provided herein
in a modified release dosage form can be fabricated as a multiparticulate
controlled release device, which comprises a multiplicity of particles,
granules, or pellets, ranging from about 10 μm to about 3 mm, about 50
μm to about 2.5 mm, or from about 100 μm to about 1 mm in diameter.
Such multiparticulates can be made by the processes known to those
skilled in the art, including wet- and dry-granulation,
extrusion/spheronization, roller-compaction, melt-congealing, and by
spray-coating seed cores. See, e.g., Multiparticulate Oral Drug Delivery;
Marcel Dekker: 1994; Pharmaceutical Pelletization Technology; Marcel
Dekker: 1989.

[0284] In one embodiment, other excipients or carriers as described herein
can be blended with the pharmaceutical compositions to aid in processing
and forming the multiparticulates. The resulting particles can themselves
constitute the multiparticulate device or can be coated by various
film-forming materials, such as enteric polymers, water-swellable, and
water-soluble polymers. The multiparticulates can be further processed as
a capsule or a tablet.

(d) Targeted Delivery

[0285] In one embodiment, the pharmaceutical compositions provided herein
can also be formulated to be targeted to a particular tissue, receptor,
or other area of the body of the subject to be treated, including
liposome-, resealed erythrocyte-, and antibody-based delivery systems.
Examples include, but are not limited to, those disclosed in U.S. Pat.
Nos. 6,316,652; 6,274,552; 6,271,359; 6,253,872; 6,139,865; 6,131,570;
6,120,751; 6,071,495; 6,060,082; 6,048,736; 6,039,975; 6,004,534;
5,985,307; 5,972,366; 5,900,252; 5,840,674; 5,759,542; and 5,709,874.

[0286] 5. Kits

[0287] In one embodiment, provided herein are kits which, when used by the
medical practitioner, can simplify the administration of appropriate
amounts of active ingredients to a subject. In certain embodiments, the
kit provided herein includes a container and a dosage form of a compound
provided herein, including a single enantiomer or a mixture of
enantiomers or diastereomers thereof; or a pharmaceutically acceptable
salt, solvate, or prodrug thereof

[0288] In certain embodiments, the kit includes a container comprising a
dosage form of the compound provided herein, including a single
enantiomer or a mixture of enantiomers or diastereomers thereof; or a
pharmaceutically acceptable salt, solvate, or prodrug thereof, in a
container comprising one or more other therapeutic agent(s) described
herein.

[0289] In one embodiment, active ingredients provided herein are not
administered to a patient at the same time or by the same route of
administration. In another embodiment, provided are kits which can
simplify the administration of appropriate amounts of active ingredients.

[0290] In one embodiment, a kit comprises a dosage form of a compound
provided herein. Kits can further comprise one or more second active
ingredients as described herein, or a pharmacologically active mutant or
derivative thereof, or a combination thereof.

[0291] In other embodiments, kits can further comprise devices that are
used to administer the active ingredients. Examples of such devices
include, but are not limited to, syringes, drip bags, patches, and
inhalers.

[0292] In one embodiment, kits can further comprise cells or blood for
transplantation as well as pharmaceutically acceptable vehicles that can
be used to administer one or more active ingredients. For example, if an
active ingredient is provided in a solid form that must be reconstituted
for parenteral administration, the kit can comprise a sealed container of
a suitable vehicle in which the active ingredient can be dissolved to
form a particulate-free sterile solution that is suitable for parenteral
administration. Examples of pharmaceutically acceptable vehicles include,
but are not limited to: Water for Injection USP; aqueous vehicles such
as, but not limited to, Sodium Chloride Injection, Ringer's Injection,
Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated
Ringer's Injection; water-miscible vehicles such as, but not limited to,
ethyl alcohol, polyethylene glycol, and polypropylene glycol; and
non-aqueous vehicles such as, but not limited to, corn oil, cottonseed
oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and
benzyl benzoate.

[0293] In one embodiment, the compounds provided herein can also be
provided as an article of manufacture using packaging materials well
known to those of skill in the art. See, e.g., U.S. Pat. Nos. 5,323,907;
5,052,558; and 5,033,252. Examples of pharmaceutical packaging materials
include, but are not limited to, blister packs, bottles, tubes, inhalers,
pumps, bags, vials, containers, syringes, and any packaging material
suitable for a selected formulation and intended mode of administration
and treatment.

E. Methods of Use

[0294] 1. In Vitro Assays and In Vivo Assays

[0295] In one embodiment, provided herein is a method of inhibiting or
reducing the activity of eIF4E. In one embodiment, the method comprises
downregulating cap-dependent protein translation initiation with a
compound provided herein, e.g., a compound of formula (I). In one
embodiment, without being limited by a particular theory, the method
comprises contacting a compound provided herein, e.g., a compound of
formula (I), with one or more molecular targets in the translation
initiation complex eIF4F, which comprises eIF4E, eIF4G (a scaffold
protein), and eIF4A (an RNA helicase). In one embodiment, without being
limited by a particular theory, the method comprises disrupting the
interaction between eIF4E and the 7-methylguanosine 5' cap with a
compound provided herein, e.g., a compound of formula (I). In one
embodiment, the method provided herein comprises selectively
downregulating cap-dependent protein translation initiation with a
compound provided herein, e.g., a compound of formula (I). In one
embodiment, the compound provided herein has minimal on-target toxicity.
In one embodiment, the compound provided herein has a large therapeutic
index. In one embodiment, the compound provided herein inhibits cancer
growth while having minimal toxicity in normal cells.

[0296] In one embodiment, the compound selectively targets the
cap-dependent protein translation pathway. In one embodiment, without
being limited by a particular theory, the compound selectively disrupts
the eIF4F complex.

[0297] In one embodiment, provided herein is a method of inhibiting or
reducing the activity of the Hedgehog pathway. In one embodiment, the
method comprises contacting one or more receptors in the Hedgehog pathway
with a compound provided herein, e.g., a compound of formula (I). In one
embodiment, the method comprises contacting Smoothened in the Hedgehog
pathway with a compound provided herein, e.g., a compound of formula (I).
In one embodiment, the method comprises contacting Patched in the
Hedgehog pathway with a compound provided herein, e.g., a compound of
formula (I).

[0298] In one embodiment, the compound selectively targets the Hedgehog
pathway.

[0299] In one embodiment, the compound selectively targets the
cap-dependent protein translation pathway and the Hedgehog pathway.

[0300] In one embodiment, provided herein are methods comprising the step
of contacting a compound provided herein with one or more cells of a
certain type of cancer, including but not limited to, breast cancer
(e.g., triple negative breast cancer, ER+ breast cancer, or ER- breast
cancer), basal cell carcinoma, skin cancer, lung cancer, small cell lung
cancer, non-small cell lung cancer, brain cancer, medulloblastoma,
glioblastoma, colorectal cancer, ovarian cancer, liver cancer, pancreatic
cancer (e.g., carcinoma, angiosarcoma, adenosarcoma), gastric cancer,
gastroesophageal junction cancer, prostate cancer, cervical cancer,
bladder cancer, head and neck cancer, lymphoma (e.g., mantle cell
lymphoma, diffuse large B-cell lymphoma), solid tumors that cannot be
removed by surgery, locally advanced solid tumors, metastatic solid
tumors, leukemia (e.g., acute myeloid leukemia (AML), acute lymphoblastic
leukemia (ALL), or chronic myeloid leukemia (CML)), or recurrent or
refractory tumors. In one embodiment, provided herein are methods
comprising the step of contacting a compound provided herein with one or
more cells of a certain type of disorder, including but not limited to,
basal cell nevus syndrome (Gorlin syndrome). In one embodiment, provided
herein are methods comprising the step of contacting a compound provided
herein with one or more cells of a certain type of disorder, including
but not limited to, basal cell carcinoma associated with Gorlin syndrome.
In certain embodiments, the methods may be conducted in vivo, in vitro,
and/or ex vivo. In certain embodiments, the methods may be conducted in
an animal, e.g., mice or rats. In certain embodiments, the methods
provided herein further comprise the step of implanting a certain cancer
cell type (e.g., breast cancer) in an animal (e.g., mice or rats) using a
method known in the art, followed by the step of treating the animal with
a compound provided herein. The time between the implanting step and the
treatment step may vary to allow the establishment and/or metastasis of
cancer in the animal.

[0302] In one embodiment, the cells are sensitive to a compound provided
herein, e.g., a compound of formula (I), or an enantiomer, a mixture of
enantiomers or a mixture of diastereomers thereof, wherein the EC50
of the compound is less than about 0.001 μM, less than about 0.005
μM, less than about 0.01 μM, less than about 0.05 μM, less than
about 0.1 μM, less than about 0.3 μM, less than about 0.5 μM,
less than about 0.7 μM, less than about 1 μM, less than about 3
μM, less than about 5 μM, less than about μM, less than about 15
μM, or less than about 30 μM. In one embodiment, the cells are
sensitive to a compound provided herein, e.g., a compound of formula (I),
or an enantiomer, a mixture of enantiomers or a mixture of diastereomers
thereof, where the EC50 of the compound is between about 0.001 μM
and about 30 μM, between about 0.01 μM and about 30 μM, between
about 0.1 μM and about 30 μM, between about 1 μM and about 30
μM, between about 3 μM and about 30 μM, or between about 10
μM and about μM. In one embodiment, the cells are sensitive to a
compound provided herein, e.g., a compound of formula (I), or an
enantiomer, a mixture of enantiomers or a mixture of diastereomers
thereof, wherein the EC50 of the compound is about 0.001 μM,
about 0.005 μM, about 0.01 μM, about 0.05 μM, about 0.1 μM,
about 0.3 μM, about 0.5 μM, about 0.7 μM, about 1 μM, about 3
μM, about 5 μM, about 10 μM, about 15 μM, about μM, or
greater than 30 μM.

[0303] 2. Treatment, Prevention, and/or Amelioration of Disorders

[0304] In one embodiment, provided herein is a method of treating,
preventing, or ameliorating one or more symptoms of a disorder mediated
by cap-dependent protein translation, comprising administering a compound
provided herein, e.g., a compound of formula (I), or an enantiomer, a
mixture of enantiomers, or a mixture of two or more diastereomers
thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or
prodrug thereof, or a pharmaceutical composition provided herein. In one
embodiment, provided herein is a method of treating, preventing, or
ameliorating one or more symptoms of a disorder mediated by eIF4E,
comprising administering a compound provided herein, e.g., a compound of
formula (I), or an enantiomer, a mixture of enantiomers, or a mixture of
two or more diastereomers thereof, or a pharmaceutically acceptable salt,
solvate, hydrate, or prodrug thereof, or a pharmaceutical composition
provided herein. A method of treating, preventing, or ameliorating one or
more symptoms of a disorder mediated by the Hedgehog pathway, comprising
administering a compound provided herein, e.g., a compound of formula
(I), or an enantiomer, a mixture of enantiomers, or a mixture of two or
more diastereomers thereof, or a pharmaceutically acceptable salt,
solvate, hydrate, or prodrug thereof, or a pharmaceutical composition
provided herein. In one embodiment, the disorder is cancer, a
proliferative disorder, breast cancer, triple negative breast cancer, ER+
breast cancer, ER- breast cancer, basal cell nevus syndrome (Gorlin
syndrome), basal cell carcinoma, skin cancer, lung cancer, small cell
lung cancer, non-small cell lung cancer, brain cancer, medulloblastoma,
glioblastoma, colorectal cancer, ovarian cancer, liver cancer, pancreatic
cancer, pancreatic carcinoma, pancreatic angiosarcoma, pancreatic
adenosarcoma, gastric cancer, gastroesophageal junction cancer, prostate
cancer, cervical cancer, bladder cancer, head and neck cancer, lymphoma,
mantle cell lymphoma, diffuse large B-cell lymphoma, solid tumors that
cannot be removed by surgery, locally advanced solid tumors, metastatic
solid tumors, leukemia, acute myeloid leukemia (AML), acute lymphoblastic
leukemia (ALL), chronic myeloid leukemia (CML), or recurrent or
refractory tumors. In one embodiment, the disorder is basal cell
carcinoma associated with Gorlin syndrome.

[0305] In one embodiment, provided herein is a method for the treatment,
prevention, or amelioration of one or more symptoms of a disorder, such
as cancer, a proliferative disorder, or a disorder mediated by
angiogenesis, in a subject, comprising administering to the subject a
therapeutically effective amount of a compound provided herein, e.g., a
compound of formula (I), or an enantiomer, a mixture of enantiomers or a
mixture of diastereomers thereof, or a pharmaceutically acceptable salt,
solvate, hydrate or prodrug thereof. In one embodiment, the subject is a
human. In one embodiment, the subject is a mammal. In one embodiment, the
subject is a rodent, such as, e.g., mice or rats. In one embodiment, the
subject is a primate. In one embodiment, the subject is a non-human
primate, a farm animal such as cattle, a sport animal such as horses, or
a pet such as dogs or cats.

[0306] In one embodiment, provided herein is use of a compound, e.g., a
compound of formula (I), or an enantiomer, a mixture of enantiomers or a
mixture of diastereomers thereof, or a pharmaceutically acceptable salt,
solvate, hydrate or prodrug thereof, or a pharmaceutical composition
comprising the compound, in the manufacture of a medicament for the
treatment, prevention, or amelioration of a disorder provided herein. In
one embodiment, provided herein is a compound, e.g., a compound of
formula (I), or an enantiomer, a mixture of enantiomers or a mixture of
diastereomers thereof, or a pharmaceutically acceptable salt, solvate,
hydrate or prodrug thereof, or a pharmaceutical composition comprising
the compound, for use in the treatment, prevention, or amelioration of a
disorder provided herein. In one embodiment, the disorder is cancer. In
one embodiment, the disorder is a proliferative disorder. In one
embodiment, provided herein is use of a compound, e.g., a compound of
formula (I), or an enantiomer, a mixture of enantiomers or a mixture of
diastereomers thereof, or a pharmaceutically acceptable salt, solvate,
hydrate or prodrug thereof, or a pharmaceutical composition comprising
the compound, in the manufacture of a medicament for the treatment of
cancer.

[0307] In one embodiment, the disorder that can be treated, prevented, or
ameliorated is a disorder, disease, or condition associated with eIF4E
levels in a subject, comprising administering to the subject a
therapeutically effective amount of a compound provided herein, e.g., a
compound of formula (I), or an enantiomer, a mixture of enantiomers or a
mixture of diastereomers thereof, or a pharmaceutically acceptable salt,
solvate, hydrate or prodrug thereof. In one embodiment, the disorder that
can be treated, prevented, or ameliorated is a disorder, disease, or
condition associated with cap-dependent protein translation initiation in
a subject, comprising administering to the subject a therapeutically
effective amount of a compound provided herein, e.g., a compound of
formula (I), or an enantiomer, a mixture of enantiomers or a mixture of
diastereomers thereof, or a pharmaceutically acceptable salt, solvate,
hydrate or prodrug thereof. In one embodiment, the disorder that can be
treated, prevented, or ameliorated is a disorder, disease, or condition
responsive to the modulation of eIF4E levels in a subject, comprising
administering to the subject a therapeutically effective amount of a
compound provided herein, e.g., a compound of formula (I), or an
enantiomer, a mixture of enantiomers or a mixture of diastereomers
thereof, or a pharmaceutically acceptable salt, solvate, hydrate or
prodrug thereof. In one embodiment, the disorder that can be treated,
prevented, or ameliorated is a disorder, disease, or condition mediated
by eIF4F complex in a subject, comprising administering to the subject a
therapeutically effective amount of a compound provided herein, e.g., a
compound of formula (I), or an enantiomer, a mixture of enantiomers or a
mixture of diastereomers thereof, or a pharmaceutically acceptable salt,
solvate, hydrate or prodrug thereof.

[0308] In one embodiment, the disorder that can be treated, prevented, or
ameliorated is a disorder, disease, or condition associated with the
activity of the Hedgehog pathway in a subject, comprising administering
to the subject a therapeutically effective amount of a compound provided
herein, e.g., a compound of formula (I), or an enantiomer, a mixture of
enantiomers or a mixture of diastereomers thereof, or a pharmaceutically
acceptable salt, solvate, hydrate or prodrug thereof. In one embodiment,
the disorder that can be treated, prevented, or ameliorated is a
disorder, disease, or condition responsive to the modulation of the
Hedgehog pathway in a subject, comprising administering to the subject a
therapeutically effective amount of a compound provided herein, e.g., a
compound of formula (I), or an enantiomer, a mixture of enantiomers or a
mixture of diastereomers thereof, or a pharmaceutically acceptable salt,
solvate, hydrate or prodrug thereof. In one embodiment, the disorder that
can be treated, prevented, or ameliorated is a disorder, disease, or
condition mediated by the Hedgehog pathway in a subject, comprising
administering to the subject a therapeutically effective amount of a
compound provided herein, e.g., a compound of formula (I), or an
enantiomer, a mixture of enantiomers or a mixture of diastereomers
thereof, or a pharmaceutically acceptable salt, solvate, hydrate or
prodrug thereof.

[0310] In one embodiment, the compounds provided herein inhibit or reduce
the activity of the hedgehog signaling pathway and are useful for the
treatment of cancers associated with aberrant hedgehog signaling, such
as, e.g., when Ptc fails to, or inadequately, represses Smo (Ptc
loss-of-function phenotype) and/or when Smo is active regardless of Ptc
repression (Smo gain-of-function phenotype). In one embodiment, examples
of such cancer types include, but are not limited to, basal cell
carcinoma, neuroectodermal tumors such as medulloblastoma, meningioma,
hemangioma, glioblastoma, pancreatic adenocarcinoma, squamous lung
carcinoma, small-cell lung carcinoma, non-small cell lung carcinoma,
chondrosarcoma, breast carcinoma, rhabdomyosarcoma, oesophageal cancer,
stomach cancer, biliary tract cancer, renal carcinoma, and thyroid
carcinoma. In one embodiment, the compounds provided herein may be
administered prior to, concomitantly with, or following the
administration of other anticancer treatments, such as, e.g., radiation
therapy or chemotherapy, as described herein elsewhere.

[0311] In one embodiment, the compounds provided herein inhibit
angiogenesis and are useful in the treatment of diseases or conditions
mediated by angiogenesis. In one embodiment, the compounds provided
herein are useful for treating tumors, e.g., solid tumors, such as, e.g.,
colon, lung, pancreatic, ovarian, breast and glioma. In one embodiment,
the compounds provided herein are useful for treating macular
degeneration, such as, e.g., wet age-related macular degeneration. In one
embodiment, the compounds provided herein are useful for treating
inflammatory/immune diseases, such as, e.g., Crohn's disease,
inflammatory bowel disease, Sjogren's syndrome, asthma, organ transplant
rejection, systemic lupus erythmatoses, rheumatoid arthritis, psoriatic
arthritis, psoriasis, and multiple sclerosis. In one embodiment, the
compounds provided herein are useful as a depilatory.

[0312] In one embodiment, the method provided herein comprises the step of
identifying in a subject the presence of a certain type of cancer. In one
embodiment, the method provided herein comprises the step of identifying
in a subject the presence of a type of cancer that is sensitive to eIF4E
modulation. In one embodiment, the method provided herein comprises the
step of identifying in a subject the presence of a type of cancer that is
sensitive to the modulation of hedgehog signaling pathway activity. In
one embodiment, the method provided herein comprises the step of
administering a compound provided herein, e.g., a compound of formula
(I), or an enantiomer, a mixture of enantiomers or a mixture of
diastereomers thereof, or a pharmaceutically acceptable salt, solvate,
hydrate or prodrug thereof, to a subject having a certain type of cancer.

[0313] In one embodiment, provided herein are methods of treating,
preventing, or ameliorating cancer in the primary tumor, in the lymph
nodes, and/or after distant metastasis, comprising administering a
compound provided herein, e.g., a compound of formula (I), or an
enantiomer, a mixture of enantiomers or a mixture of diastereomers
thereof, or a pharmaceutically acceptable salt, solvate, hydrate or
prodrug thereof, to a subject in need thereof. In one embodiment,
provided herein are methods of treating, preventing, or ameliorating
cancer in the primary tumor, comprising administering a compound provided
herein, e.g., a compound of formula (I), or an enantiomer, a mixture of
enantiomers or a mixture of diastereomers thereof, or a pharmaceutically
acceptable salt, solvate, hydrate or prodrug thereof, to a subject in
need thereof. In one embodiment, provided herein are methods of treating,
preventing, or ameliorating cancer in the lymph nodes, comprising
administering a compound provided herein, e.g., a compound of formula
(I), or an enantiomer, a mixture of enantiomers or a mixture of
diastereomers thereof, or a pharmaceutically acceptable salt, solvate,
hydrate or prodrug thereof, to a subject in need thereof. In one
embodiment, provided herein are methods of treating, preventing, or
ameliorating cancer after distant metastasis, comprising administering a
compound provided herein, e.g., a compound of formula (I), or an
enantiomer, a mixture of enantiomers or a mixture of diastereomers
thereof, or a pharmaceutically acceptable salt, solvate, hydrate or
prodrug thereof, to a subject in need thereof.

[0314] In one embodiment, provided herein are methods of treating,
preventing, or ameliorating cancer in a subject having surgically
resectable cancer, locally advanced cancer, regionally advanced cancer,
and/or distant metastatic cancer, comprising administering a compound
provided herein, e.g., a compound of formula (I), or an enantiomer, a
mixture of enantiomers or a mixture of diastereomers thereof, or a
pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, to
a subject in need thereof. In one embodiment, provided herein are methods
of treating, preventing, or ameliorating cancer in a subject having
surgically resectable cancer, comprising administering a compound
provided herein, e.g., a compound of formula (I), or an enantiomer, a
mixture of enantiomers or a mixture of diastereomers thereof, or a
pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, to
a subject in need thereof. In one embodiment, provided herein are methods
of treating, preventing, or ameliorating cancer in a subject having
locally advanced cancer, comprising administering a compound provided
herein, e.g., a compound of formula (I), or an enantiomer, a mixture of
enantiomers or a mixture of diastereomers thereof, or a pharmaceutically
acceptable salt, solvate, hydrate or prodrug thereof, to a subject in
need thereof. In one embodiment, provided herein are methods of treating,
preventing, or ameliorating cancer in a subject having regionally
advanced cancer, comprising administering a compound provided herein,
e.g., a compound of formula (I), or an enantiomer, a mixture of
enantiomers or a mixture of diastereomers thereof, or a pharmaceutically
acceptable salt, solvate, hydrate or prodrug thereof, to a subject in
need thereof. In one embodiment, provided herein are methods of treating,
preventing, or ameliorating cancer in a subject having distant metastatic
cancer, comprising administering a compound provided herein, e.g., a
compound of formula (I), or an enantiomer, a mixture of enantiomers or a
mixture of diastereomers thereof, or a pharmaceutically acceptable salt,
solvate, hydrate or prodrug thereof, to a subject in need thereof.

[0315] In one embodiment, provided herein are methods of treating,
preventing, or ameliorating breast cancer comprising administering a
compound provided herein, e.g., a compound of formula (I), or an
enantiomer, a mixture of enantiomers or a mixture of diastereomers
thereof, or a pharmaceutically acceptable salt, solvate, hydrate or
prodrug thereof, to a subject having breast cancer. In one embodiment,
provided herein is a method of treating, preventing, or ameliorating
triple negative breast cancer comprising administering a compound
provided herein, e.g., a compound of formula (I), or an enantiomer, a
mixture of enantiomers or a mixture of diastereomers thereof, or a
pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.

[0316] In one embodiment, provided herein are methods of treating,
preventing, or ameliorating certain stages of breast cancer, including
but not limited to, Stage O, Stage I, Stage IIA, Stage IIB, Stage IIIA,
Stage IIIB, Stage IIIC, and Stage 1V, by administering a compound
provided herein, e.g., a compound of formula (I), or an enantiomer, a
mixture of enantiomers or a mixture of diastereomers thereof, or a
pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, to
a subject in need thereof. The staging of breast cancer may be defined
according to methods known in the art, for example, according to the
guidelines provided by the American Joint Committee on Cancer (AJCC). In
one embodiment, the staging of breast cancer is designated and grouped
based on the TNM classification, i.e., a classification based on the
status of primary tumor (e.g., TX, T0, Tis, T1, T2, T3, T4), regional
lymph nodes (e.g., NX, N0, N1, N2, N3), and/or distant metastasis (e.g.,
MX, M0, M1), in a subject having breast cancer. See, e.g., Breast in:
American Joint Committee on Cancer: AJCC Cancer Staging Manual, 6th ed.,
New York, N.Y., Springer, 2002, 171-80.

[0317] In one embodiment, provided herein are methods for treating
subjects having breast cancer, including, e.g., particular breast cancer
subtypes, using a compound provided herein, e.g., a compound of formula
(I), or an enantiomer, a mixture of enantiomers or a mixture of
diastereomers thereof, or a pharmaceutically acceptable salt, solvate,
hydrate or prodrug thereof. In one embodiment, the tumor is estrogen
receptor-negative, progesterone receptor-negative and HER2-negative. In
one embodiment, provided herein are methods comprising the step of
identifying in a subject the presence of a particular type of breast
cancer, including e.g., triple negative breast cancer, and the step of
administering a compound provided herein, e.g., a compound of formula
(I), or an enantiomer, a mixture of enantiomers or a mixture of
diastereomers thereof, or a pharmaceutically acceptable salt, solvate,
hydrate or prodrug thereof, to the subject.

[0320] Particular embodiments provide treating a subject having cancer
using one or more of the methods provided herein, together with surgery.
Particular embodiments provide treating a subject having cancer using one
or more of the methods provided herein, together with chemotherapy.
Particular embodiments provide treating a subject having cancer using one
or more of the methods provided herein, together with immunotherapy.
Particular embodiments provide treating a subject having cancer using one
or more of the methods provided herein, together with targeted therapy.
Particular embodiments provide treating a subject having cancer using one
or more of the methods provided herein, together with radiation therapy.
Particular embodiments provide treating a subject having cancer using one
or more of the methods provided herein, together with two or more of the
treatments selected from surgery, chemotherapy, immunotherapy, targeted
therapy, and radiation therapy.

[0321] In certain embodiments, the subject to be treated with one of the
methods provided herein has not been treated with anticancer therapy
prior to the administration of a compound provided herein. In certain
embodiments, the subject to be treated with one of the methods provided
herein has been treated with one or more anticancer therapies prior to
the administration of a compound provided herein. In certain embodiments,
the subject to be treated with one of the methods provided herein has
been treated with a cancer therapeutic agent, as described herein. In
certain embodiments, the subject to be treated with one of the methods
provided herein has developed drug resistance to anticancer therapy. In
certain embodiments, the subject to be treated with the methods provided
herein has a relapsed cancer. In certain embodiments, the subject to be
treated with the methods provided herein has a refractory cancer. In
certain embodiments, the subject to be treated with the methods provided
herein has a metastatic cancer.

[0322] In one embodiment, provided herein are methods for treating a
subject having a cancer, comprising administering to the subject a
therapeutically effective amount of a compound provided herein, e.g., a
compound of formula (I), or an enantiomer, a mixture of enantiomers or a
mixture of diastereomers thereof, or a pharmaceutically acceptable salt,
solvate, hydrate or prodrug thereof; wherein the cancer is resistant to
conventional therapy (e.g., resistant to other anticancer drugs). In one
embodiment, the cancer treated by a compound provided herein, e.g., a
compound of formula (I), is resistant to one or more anticancer drug(s),
including, but not limited to, vincristine, taxol, cytarabine, and/or
doxorubicin. In one embodiment, the cancer is resistant to a therapeutic
agent described herein (e.g., Section E.5, infra). In one embodiment, the
cancer is vincristine-resistant. In one embodiment, the cancer is
taxol-resistant. In one embodiment, the cancer is cytarabine-resistant.
In one embodiment, the cancer is doxorubicin-resistant. In one
embodiment, the cancer is resistant to a therapeutic agent that modulates
microtubule formation. In one embodiment, the cancer is resistant to a
therapeutic agent that is associated with p-glycoprotein mediated
multidrug resistance.

[0323] In one embodiment, the methods provided herein encompass treating a
subject regardless of patient's age, although some diseases or disorders
are more common in certain age groups. Further provided herein is a
method for treating a subject who has undergone surgery in an attempt to
treat the disease or condition at issue. Further provided herein is a
method for treating a subject who has not undergone surgery as an attempt
to treat the disease or condition at issue. Because the subjects with
cancer have heterogeneous clinical manifestations and varying clinical
outcomes, the treatment given to a particular subject may vary, depending
on his/her prognosis. The skilled clinician will be able to readily
determine without undue experimentation, specific secondary agents, types
of surgery, and types of non-drug based standard therapy that can be
effectively used to treat an individual subject with cancer.

[0324] In each embodiment provided herein, the method may further comprise
one or more diagnostic steps, to determine, e.g., the type of cancer, the
presence of particular cell types, and/or the staging of the disease in a
subject.

[0325] In each embodiment provided herein, the method may further comprise
a disease evaluation step after the compound or pharmaceutical
composition has been administered to the subject, to determine, e.g.,
changes in one or more molecular markers as described herein elsewhere,
changes in tumor size and location, and/or other benchmarks used by those
skilled in the art to determine the prognosis of cancer in a subject.

[0326] 3. Biomarkers

[0327] In certain embodiments, appropriate biomarkers may be used to
determine or predict the effect of the methods provided herein on the
disease state and to provide guidance as to the dosing schedule and
dosage amount. In particular embodiments, the greater benefit is an
overall survival benefit. In particular embodiments, the greater benefit
is tumor stasis and remission. In particular embodiments, the greater
benefit is prevention of tumor recurrence. In one embodiment, provided
herein is a method for determining whether a patient diagnosed with
cancer has an increased probability of obtaining a greater benefit from
treatment with a compound provided herein by assessing the level of eIF4E
in the tumor biopsy samples obtained from the patient. In one embodiment,
provided herein is a method for determining whether a patient diagnosed
with cancer has an increased probability of obtaining a greater benefit
from treatment with a compound provided herein by assessing the
sensitivity of cancer cells obtained from the patient to the
downregulation of cap-dependent protein translation initiation. In one
embodiment, the method comprises assessing the activity of a compound
provided herein in tumor biopsy samples in vitro. In one embodiment, the
method comprises assessing the levels of one or more growth factors
and/or cytokines that are important in cancer progression and weakly
translated. In one embodiment, the growth factor markers and cytokine
markers include, but are not limited to, VEFG, FGF, IL-1, and TGF-β.
In one embodiment, provided herein is a method for determining the
response of a patient to the treatment of a compound provided herein, by
assessing one or more of the molecular biomarkers described herein. In
one embodiment, the dosage of a compound used in treating a patient is
adjusted based on the result of biomarker responses in the particular
patient after initial treatment with the compound.

[0328] 4. Administration of Compounds

[0329] Depending on the disorder, disease, or condition to be treated, and
the subject's condition, the compounds or pharmaceutical compositions
provided herein can be administered by oral, parenteral (e.g.,
intramuscular, intraperitoneal, intravenous, ICV, intracistemal injection
or infusion, subcutaneous injection, or implant), inhalation, nasal,
vaginal, rectal, sublingual, or topical (e.g., transdermal or local)
routes of administration and can be formulated, alone or together, in
suitable dosage unit with pharmaceutically acceptable excipients,
carriers, adjuvants, and vehicles appropriate for each route of
administration. Also provided is administration of the compounds or
pharmaceutical compositions provided herein in a depot formulation, in
which the active ingredient is released over a predefined time period. In
one embodiment, the compound or composition is administered orally. In
another embodiment, the compound or composition is administered
parenterally. In yet another embodiment, the compound or composition is
administered intravenously.

[0330] Certain methods herein provide the administration of a compound
provided herein by intravenous (IV), subcutaneous (SC) or oral routes
administration. Certain embodiments herein provide co-administration of a
compound provided herein with one or more additional active agents to
provide a synergistic therapeutic effect in subjects in need thereof. The
co-administered agent(s) may be a cancer therapeutic agent, as described
herein. In certain embodiments, the co-administered agent(s) may be
dosed, e.g., orally or by injection (e.g., IV or SC).

[0331] Certain embodiments herein provide methods for treating disorders
of abnormal cell proliferation comprising administering a compound
provided herein using, e.g., IV, SC and/or oral administration methods.
In certain embodiments, treatment cycles comprise multiple doses
administered to a subject in need thereof over multiple days (e.g., 1, 2,
3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or greater than 14 days),
optionally followed by treatment dosing holidays (e.g., 1, 2, 3, 4, 5, 6,
7, 8, 9, 10, 11, 12, 13, 14, or greater than 14 days). Suitable dosage
amounts for the methods provided herein include, e.g., therapeutically
effective amounts and prophylactically effective amounts. For example, in
certain embodiments, the amount of a compound provided herein
administered in the methods provided herein may range, e.g., between
about 10 mg/day and about 2,000 mg/day, between about 20 mg/day and about
1,000 mg/day, between about 50 mg/day and about 1,000 mg/day, between
about 100 mg/day and about 1,000 mg/day, between about 100 mg/day and
about 500 mg/day, between about 100 mg/day and about 200 mg/day, or
between about 200 mg/day and about 500 mg/day. In certain embodiments,
particular dosages are, e.g., up to about 10 mg/day, up to about 20
mg/day, up to about 40 mg/day, up to about 60 mg/day, up to about 80
mg/day, up to about 100 mg/day, up to about 120 mg/day, up to about 140
mg/day, up to about 150 mg/day, up to about 160 mg/day, up to about 180
mg/day, up to about 200 mg/day, up to about 220 mg/day, up to about 240
mg/day, up to about 250 mg/day, up to about 260 mg/day, up to about 280
mg/day, up to about 300 mg/day, up to about 320 mg/day, up to about 350
mg/day, up to about 400 mg/day, up to about 450 mg/day, up to about 500
mg/day, up to about 750 mg/day, or up to about 1000 mg/day. In certain
embodiments, particular dosages are, e.g., about 10 mg/day, about 20
mg/day, about 50 mg/day, about 75 mg/day, about 100 mg/day, about 120
mg/day, about 150 mg/day, about 200 mg/day, about 250 mg/day, about 300
mg/day, about 350 mg/day, about 400 mg/day, about 450 mg/day, about 500
mg/day, about 600 mg/day, about 700 mg/day, about 800 mg/day, about 900
mg/day, about 1,000 mg/day, about 1,200 mg/day, or about 1,500 mg/day.

[0332] In one embodiment, the amount of a compound provided herein in the
pharmaceutical composition or dosage form provided herein may range,
e.g., between about 5 mg and about 2,000 mg, between about 10 mg and
about 2,000 mg, between about 20 mg and about 2,000 mg, between about 50
mg and about 1,000 mg, between about 100 mg and about 500 mg, between
about 150 mg and about 500 mg, or between about 150 mg and about 250 mg.
In certain embodiments, the amount of a compound provided herein in the
pharmaceutical composition or dosage form provided herein is, e.g., about
10 mg, about 20 mg, about 50 mg, about 75 mg, about 100 mg, about 120 mg,
about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg,
about 400 mg, about 450 mg, about 500 mg, about 600 mg, about 700 mg,
about 800 mg, about 900 mg, about 1,000 mg, about 1,200 mg, or about
1,500 mg. In certain embodiments, the amount of a compound provided
herein in the pharmaceutical composition or dosage form provided herein
is, e.g., up to about 10 mg, up to about 20 mg, up to about 50 mg, up to
about 75 mg, up to about 100 mg, up to about 120 mg, up to about 150 mg,
up to about 200 mg, up to about 250 mg, up to about 300 mg, up to about
350 mg, up to about 400 mg, up to about 450 mg, up to about 500 mg, up to
about 600 mg, up to about 700 mg, up to about 800 mg, up to about 900 mg,
up to about 1,000 mg, up to about 1,200 mg, or up to about 1,500 mg.

[0333] In one embodiment, the compound or composition can be delivered as
a single dose such as, e.g., a single bolus injection, or oral tablets or
pills; or over time such as, e.g., continuous infusion over time or
divided bolus doses over time. In one embodiment, the compound or
composition can be administered repetitively if necessary, for example,
until the patient experiences stable disease or regression, or until the
patient experiences disease progression or unacceptable toxicity. For
example, stable disease for solid tumors generally means that the
perpendicular diameter of measurable lesions has not increased by 25% or
more from the last measurement. See, e.g., Response Evaluation Criteria
in Solid Tumors (RECIST) Guidelines, Journal of the National Cancer
Institute 92(3): 205-216 (2000). Stable disease or lack thereof is
determined by methods known in the art such as evaluation of patient's
symptoms, physical examination, visualization of the tumor that has been
imaged using X-ray, CAT, PET, or MRI scan and other commonly accepted
evaluation modalities.

[0334] In one embodiment, the compound or composition can be administered
once daily (QD), or divided into multiple daily doses such as twice daily
(BID), three times daily (TID), and four times daily (QID). In one
embodiment, the administration can be continuous (i.e., daily for
consecutive days or every day), intermittent, e.g., in cycles (i.e.,
including days, weeks, or months of rest when no drug is administered).
In one embodiment, the compound or composition is administered daily, for
example, once or more than once each day for a period of time. In one
embodiment, the compound or composition is administered daily for an
uninterrupted period of at least 7 days, in some embodiments, up to 52
weeks. In one embodiment, the compound or composition is administered
intermittently, i.e., stopping and starting at either regular or
irregular intervals. In one embodiment, the compound or composition is
administered for one to six days per week. In one embodiment, the
compound or composition is administered in cycles (e.g., daily
administration for two to eight consecutive weeks, then a rest period
with no administration for up to one week). In one embodiment, the
compound or composition is administered on alternate days. In one
embodiment, the compound or composition is administered in cycles (e.g.,
administered daily or continuously for a certain period interrupted with
a rest period).

[0335] In one embodiment, the frequency of administration ranges from
about daily to about monthly. In certain embodiments, the compound or
composition is administered once a day, twice a day, three times a day,
four times a day, once every other day, twice a week, once every week,
once every two weeks, once every three weeks, or once every four weeks.

[0336] In one embodiment, the compound or composition is administered
daily from one day to six months, from one week to three months, from one
week to four weeks, from one week to three weeks, or from one week to two
weeks. In certain embodiments, the compound or composition is
administered daily for one week, two weeks, three weeks, or four weeks.
In one embodiment, the compound or composition is administered once per
day for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about
6 weeks, about 9 weeks, about 12 weeks, about 15 weeks, about 18 weeks,
about 21 weeks, or about 26 weeks. In certain embodiments, the compound
or composition is administered intermittently. In certain embodiments,
the compound or composition is administered continuously. In certain
embodiments, the compound or composition is administered to a subject in
cycles. Cycling therapy involves the administration of an active agent
for a period of time, followed by a rest for a period of time, and
repeating this sequential administration. Cycling therapy can reduce the
development of resistance, avoid or reduce the side effects, and/or
improves the efficacy of the treatment.

[0337] It is understood that the duration of the treatment may vary with
the age, weight, and condition of the subject being treated, and may be
determined empirically using known testing protocols or according to the
professional judgment of the person providing or supervising the
treatment. The skilled clinician will be able to readily determine,
without undue experimentation, an effective drug dose and treatment
duration, for treating an individual subject having a particular type of
cancer.

[0340] In one embodiment, the second therapeutic agent is an anticancer
agent. In one embodiment, the anticancer agent is an antimetabolite,
including, but not limited to, 5-fluoro uracil, methotrexate, cytarabine,
high dose cytarabine, and fludarabine. In one embodiment, the anticancer
agent is an antimicrotubule agent, including, but not limited to, vinca
alkaloids (e.g., vincristine and vinblastine) and taxanes (e.g.,
paclitaxel and docetaxel). In one embodiment, the anticancer agent is an
alkylating agent, including, but not limited to, cyclophosphamide,
melphalan, carmustine, and nitrosoureas (e.g., hydroxyurea and
bischloroethylnitrosurea). In one embodiment, the anticancer agent is a
platinum agent, including, but not limited to, cisplatin, carboplatin,
oxaliplatin, satraplatin (JM-216), and CI-973. In one embodiment, the
anticancer agent is an anthracycline, including, but not limited to,
doxrubicin and daunorubicin. In one embodiment, the anticancer agent is
an antitumor antibiotic, including, but not limited to, mitomycin,
idarubicin, adriamycin, and daunomycin (also known as daunorubicin). In
one embodiment, the anticancer agent is a topoisomerase inhibitor, e.g.,
etoposide and camptothecins. In one embodiment, the anticancer agent is
selected from the group consisting of adriamycin, busulfan, cytarabine,
cyclophosphamide, dexamethasone, fludarabine, fluorouracil, hydroxyurea,
interferons, oblimersen, platinum derivatives, taxol, topotecan, and
vincristine.

[0341] In one embodiment, the route of the administration of the compound
provided herein is independent of the route of the administration of a
second therapy. In one embodiment, the compound provided herein is
administered orally. In another embodiment, the compound provided herein
is administered intravenously. In accordance with these embodiments,
i.e., administering the compound provided herein orally or intravenously,
the second therapy can be administered orally, parenterally,
intraperitoneally, intravenously, intraarterially, transdermally,
sublingually, intramuscularly, rectally, transbuccally, intranasally,
liposomally, via inhalation, vaginally, intraoccularly, via local
delivery by catheter or stent, subcutaneously, intraadiposally,
intraarticularly, intrathecally, or in a slow release dosage form. In one
embodiment, the compound provided herein and a second therapy are
administered by the same mode of administration, e.g., orally or
intravenously. In another embodiment, the compound provided herein is
administered by one mode of administration, e.g., orally, whereas the
second agent (e.g., an anticancer agent) is administered by another mode
of administration, e.g., intravenously. In another embodiment, the
compound provided herein is administered by one mode of administration,
e.g., intravenously, whereas the second agent (e.g., an anticancer agent)
is administered by another mode of administration, e.g., orally.

[0344] Certain embodiments are illustrated by the following non-limiting
examples.

[0345] A. Synthesis of Compounds

[0346] In the examples below, unless otherwise indicated, all temperatures
are set forth in degrees Celsius and all parts and percentages are by
weight. Reagents may be purchased from commercial suppliers, such as
Sigma-Aldrich Chemical Company, and may be used without further
purification unless otherwise indicated. Reagents may also be prepared
following standard literature procedures known to those skilled in the
art. Solvents may be purchased from Aldrich in Sure-Seal bottles and used
as received. All solvents may be purified using standard methods known to
those skilled in the art, unless otherwise indicated.

[0347] The reactions set forth below were done generally at ambient
temperature, unless otherwise indicated. In one embodiment, the reaction
flasks were fitted with rubber septa for introduction of substrates and
reagents via syringe. In one embodiment, analytical thin layer
chromatography (TLC) was performed using glass-backed silica gel
pre-coated plates (Merck Art 5719) and eluted with appropriate solvent
ratios (v/v). In one embodiment, reactions were assayed by TLC, HPLC, or
LCMS, and terminated as judged by the consumption of starting material.
In one embodiment, visualization of the TLC plates was done with UV light
(254 wavelength) or with an appropriate TLC visualizing solvent, such as
basic aqueous KMnO4 solution activated with heat. In one embodiment,
flash column chromatography (See, e.g., Still et al., J. Org. Chem., 43:
2923 (1978)) was performed using silica gel 60 (Merck Art 9385) or
various MPLC systems.

[0348] The compound structures in the examples below were confirmed by one
or more of the following methods: proton magnetic resonance spectroscopy,
mass spectroscopy, elemental microanalysis, and melting point. In one
embodiment, proton magnetic resonance (1H-NMR) spectra were
determined using a NMR spectrometer operating at a certain field
strength. Chemical shifts are reported in parts per million (ppm,
δ) downfield from an internal standard, such as TMS. Alternatively,
1H-NMR spectra were referenced to signals from residual protons in
deuterated solvents as follows: CDCl3=7.25 ppm; DMSO-d6=2.49
ppm; C6D6=7.16 ppm; CD3OD=3.30 ppm. Peak multiplicities
are designated as follows: s, singlet; d, doublet; dd, doublet of
doublets; t, triplet; dt, doublet of triplets; q, quartet; br, broadened;
and m, multiplet. Coupling constants are given in Hertz (Hz). In one
embodiment, mass spectra (MS) data were obtained using a mass
spectrometer with APCI or ESI ionization.

[0360] Oxalyl chloride (0.112 mL) was added to
5-phenyl-2-trifluoromethyl-furan-3-carboxylic acid (0.153 g) in
dichloromethane (10 mL) under nitrogen, followed by the addition of a
drop of dimethylformamide. After stirring at room temperature for 1 hour,
the reaction mixture was concentrated under vacuum. To this was added
dichloromethane (5 mL) and a solution of
3-fluoro-5-trifluoromethyl-phenylamine (0.102 g) and
N,N-diisopropylethylamine (0.103 mL) in dichloromethane (5 mL). After
stirring at room temperature for 1 day, the reaction underwent an aqueous
acidic (dilute HCl, 2×15 mL) and basic (dilute NaHCO3,
2×15 mL) workup followed by washing with brine (saturated NaCl,
2×15 mL), drying over MgSO4, and concentration. The crude
compound was purified by column chromatography eluting with hexanes/ethyl
acetate (4:1) to afford the title compound (0.118 g, 47% yield). ES-MS
negative Q1 (m/z) 416.

[0362] Oxalyl chloride (0.112 mL) was added to
5-(4-bromo-phenyl)-2-trifluoromethyl-furan-3-carboxylic acid (0.200 g) in
dichloromethane (10 mL) under nitrogen, followed by the addition of a
drop of dimethylformamide. After stirring at room temperature for 1 hour,
the reaction mixture was concentrated under vacuum. To this was added
dichloromethane (5 mL) and a solution of
3-fluoro-5-trifluoromethyl-phenylamine (0.102 g) and
N,N-diisopropylethylamine (0.103 mL) in dichloromethane (5 mL). After
stirring at room temperature for 1 day, the reaction underwent an aqueous
acidic (dilute HCl, 2×15 mL) and basic (dilute NaHCO3,
2×15 mL) workup followed by washing with brine (saturated NaCl,
2×15 mL), drying over MgSO4, and concentration. The crude
compound was purified by column chromatography eluting with hexanes/ethyl
acetate (4:1) to afford the title compound (0.083 g, 28% yield). ES-MS
negative Q1 (m/z) 495.

[0364] Oxalyl chloride (0.005 mL) was added to
5-(4-methoxy-phenyl)-2-trifluoromethyl-furan-3-carboxylic acid (0.010 g)
in dichloromethane (3 mL) under nitrogen, followed by the addition of a
drop of dimethylformamide. After stirring at room temperature for 1 hour,
the reaction mixture was concentrated under vacuum. To this was added
dichloromethane (2 mL) and a solution of
3,5-bis-trifluoromethyl-phenylamine (0.008 g) and 1 drop of
N,N-diisopropylethylamine in dichloromethane (2 mL). After stirring at
room temperature for 1 day, the reaction underwent an aqueous acidic
(dilute HCl, 2×5 mL) and basic (dilute NaHCO3, 2×5 mL)
workup followed by washing with brine (saturated NaCl, 2×5 mL),
drying over MgSO4, and concentration. The crude compound was
purified by column chromatography eluting with hexanes/ethyl acetate
(6:1) to afford the title compound (0.008 g, 49% yield). ES-MS negative
Q1 (m/z) 496.

[0365] B. Determination of IC50 in Cell-Based Assays

[0366] In one embodiment, the IC50s of the compounds provided herein
were determined in cell-based assays using adherent cells. In one
embodiment, the activity of the compounds provided herein were determined
in a cell-based assay using the triple negative breast cancer cell line
MDA-MB-468. In one embodiment, the adherent cells used in the cell-based
assays may be a cell type selected from Table 1. In one embodiment, the
cell-based assay may be carried out as provided herein. On day 0, cells
were seeded at 20,000 cells per well in 100 L of media into individual
wells of a 96-well tissue culture plate. The next day, compounds were
diluted to twice the desired final concentration and added in 100 L of
media for a final volume of 200 μL. Standard solutions for each
compound were prepared at 1000× concentration in DMSO. The highest
concentration was 30 mM. Serial 1:1 dilutions were made from there for a
6- or 9-point curve (e.g., 30 mM, 15 mM, 7.5 mM, etc). Compounds were
then diluted 1:500 in media, and 100 L of the resulting solution was
added to each well for a final dilution of 1:1000. Each concentration of
compound was tested in triplicate. Cells were incubated at 37° C.
with 5% CO2. After 72 hours, 20 μL of CellTiter 96 Aqueous One
Solution Cell Proliferation Assay (Promega) was added to each well. Cells
were placed back in the incubator, and the absorbance at 490 nm was read
after 2-3 hours. The concentration of compound that decreased the number
of metabolically active cells by 50% was determined and reported as the
IC50. "Percent Viability" was determined by subtracting the average
background value (media only) and expressed as a ratio to the average
value obtained from cells treated with only DMSO.

[0367] The compounds provided herein were tested in a panel of cell-based
assays of adherent cell types. The data is summarized in Table 1.

[0368] In one embodiment, the IC50s of the compounds provided herein
were determined in cell-based assays using suspension cells. In one
embodiment, the activity of the compounds provided herein were determined
in a cell-based assay using the JeKo-1 cell line (mantle cell lymphoma)
or the Pfeiffer cell line (diffuse large B-cell lymphoma). In one
embodiment, the suspension cells used in the cell-based assays may be a
cell type selected from Table 2. Assays with suspension cells were
similar except that 40,000-60,000 cells were added to each well and
compounds were added immediately after cell plating.

[0369] The compounds provided herein were tested in a panel of cell-based
assays of suspension cell types. The data is summarized in Table 2.

[0372] In one embodiment, the effects of a compound provided herein on
tumor growth in a mouse animal model were evaluated. In specific
embodiments, the mouse animal model was the MDA-MB-468 xenograft model
for breast cancer. Studies were performed to evaluate the effect of a
compound provided herein on the growth of MDA-MB-468 breast tumors in
mice. The test system that was used is summarized below:

[0373] Animals were housed 10 mice per cage in micro-isolators, with
sterile corn cob bedding, food, and water. Mice were acclimated for 3
days and given food and tap water ad libitum. Animals were examined prior
to initiation of the study to assure adequate health and suitability.
Animals that were found to be diseased or unsuitable were not assigned to
the study. During the course of the study, 12-hour light/12-hour dark
cycle were maintained. A nominal temperature range of 20-23° C.
with a relative humidity between 30% and 70% was maintained. LabDiet
5053-certified PicoLab Rodent Diet and sterile water were provided ad
libitum during the study.

[0374] Exemplary Protocol: Ten mice per group were inoculated s.c. on the
left flank with 5×106 MDA-MB-468 cells. When tumors reached a
mean volume of 100 or 200 mm3, animals began treatment with a
compound provided herein (See Table 4). Test article or vehicle were
given once daily by IP injection for up to 21 days. Tumors were evaluated
every Monday, Wednesday and Friday, body weights and condition were
evaluated on a daily basis.

[0375] Cell Culture: MDA-MB-468 breast cancer cells were grown in
Liebowitz's L-15 with 10% fetal bovine serum and 1% pen/strep. Cells were
routinely trypsinized and passaged 1:4. On the day of implantation, cells
were washed in PBS, trypsinized and resuspended in complete media. Cells
were washed 3× in serum free media (centrifuged 1000 rpm for 5
min). Cells were resuspended to a density of 1×108 cells/mL
and diluted 1:1 with Matrigel. Cells were implanted s.c. using a 23 G
needle in a volume of 0.1 mL.

[0376] Tumor Measurement: Tumors were monitored daily. If, during a daily
evaluation, an animal's tumor appeared to have exceeded 1500 mm3,
the tumor was measured; and animals with tumors greater than 1500
mm3 and/or that had become necrotic and/or hindered movement were
euthanized. Tumors were measured twice weekly by measuring each tumor in
2 dimensions, along the largest dimension (length, L) and perpendicular
to this dimension (width, W). Tumor weights were calculated using the
standard formula: (L×W2)/2. The mean tumor weight and standard
error of the mean were calculated for each group at each time point. An
ANOVA was used to compare differences of primary tumor volume.

[0377] Animal Weight: All animals were weighed twice weekly throughout the
study. Group weight change was expressed as a daily group mean weight.
Animals that lost greater than 20% of their total starting body weight
were euthanized.

[0378] Compound 1 was dosed in mice at a dose of, for example, qd 50
mg/kg, for 22 days or more. The tumor growth inhibition data is
summarized in FIG. 1 and Tables 5 and 6.

[0379] Compound 2 was dosed in mice at a dose of, for example, qd 20 mg/kg
from day 0 to 7, then qd 10 mg/kg from day 8 and thereafter, for 22 days
or more. The tumor growth inhibition data is summarized in FIG. 1 and
Tables 5 and 6.

[0380] The examples set forth above are provided to give those of ordinary
skill in the art with a complete disclosure and description of how to
make and use the claimed embodiments, and are not intended to limit the
scope of what is disclosed herein. Modifications that are obvious to
persons of skill in the art are intended to be within the scope of the
following claims. All publications, patents, and patent applications
cited in this specification are incorporated herein by reference as if
each such publication, patent or patent application were specifically and
individually indicated to be incorporated herein by reference in their
entireties.